Search for new pharmacophores for antimalarial activity. Part I: Synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides

Bioorganic & Medicinal Chemistry 17 (2009) 203–221

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Bioorganic & Medicinal Chemistry

journal homepage: w ww.elsevier.com/locate/bmc

Search for new pharmacophores for antimalarial activity. Part I: Synthesis

and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides

S. Madapa ^a, Z. Tusi ^a, D. Sridhar ^a, A. Kumar ^b, M. I. Siddiqi ^b, K. Srivastava ^c, A. Rizvi ^c, R. Tripathi ^c,

S. K. Puri ^c, G. B. Shiva Keshava ^d, P. K. Shukla ^d, S. Batra ^a,

*

^aMedicinal and Process Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow, UP 226001, India

^bMolecular and Structural Biology Division, Central Drug Research Institute, PO Box 173, Lucknow, UP 226001, India

^cParasitology Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, USA

^dFermentation Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, USA

a r t i c l e i n f o

a b s t r a c t

Article history:

A total of 80 new 2-methyl-6-ureido-4-quinolinamides were synthesized and evaluated for their antima-

larial activity. Several analogs elicited the antimalarial effect at MIC of 0.25 mg/mL against the chlooqu-

ine-sensitive P. falciparum strain. The IC₅₀values of the active compounds were observed to be in ng/mL

range and two of the analogs have better IC₅₀value than the standard chloroquine. In the in vivo assay

against mdr CQ resistant P. yoelii N67/P. yoelii nigeriensis, however, none of the compound showed com-

plete suppression of parasitemia on day 7. One of the compounds displayed signiﬁcant antibacterial effect

against several strains of bacteria and was many-fold better than the standard drug gentamicin.

Received 23 September 2008

Revised 4 November 2008

Accepted 4 November 2008

Available online 18 November 2008

Keywords:

Quinoline

Antimalarial

Urea

In vitro

Docking

1. Introduction

the urea derivatives interact with the DHFR through hydrogen

bonding, other workers have proposed that the urea derivatives

The health problem caused by malaria, one of the most lethal of

the parasitic diseases, is now compounded due to the emergence of

strains of Plasmodium which show resistance to the known

chemotherapeutic agents. The artemisinin and its derivatives or

their combinations have now replaced the chloroquine (CQ) and

other quinoline antimalarials especially in the endemic areas.

However lower abundance and high cost of artemisinin and related

products motivate the medicinal chemists to search for new chem-

ical pharmacophores which may prove effective as antimalarials.

In this context Restelli et al. have earlier disclosed dihydrofolate

reductase (DHFR) inhibitors belonging to several new unrelated

chemical classes from the docking studies of the ACD database

with the DHFR domain of DHFR-TS, a validated target of antimalar-

ial antifolates.¹Amongst the several chemical classes having the

potential to display the antimalarial activity disclosed in this

report included the urea derivatives. Urea derivatives have been

independently also well represented in the literature to elicit

potent antimalarial activity.²Prototype structures of some of the

ureides possessing signiﬁcant in vitro antimalarial activity are pre-

sented in Figure 1. Although Rastelli and co-workers proposed that

accumulate in the food vacuole and inhibit the plasmepsin of the

parasite.^2dIn our program aimed at discovery of antimalarial

activity in new structural prototypes we carried out the synthesis

of novel 2-methyl-6-ureido-4-quinolinamide derivatives and

investigated the in vitro antimalarial efﬁcacy of the generated

compounds. Simultaneously the docking scores of these com-

pounds with the PfDHFR were investigated. These studies resulted

in discovery of several new compounds exhibiting potent in vitro

antimalarial effect. Based on the literature³precedence that aryl

urea display signiﬁcant antibacterial activity these compounds

were also investigated for their antibacterial efﬁcacy. Results of

our study on synthesis and bioactivity of new urea derivatives

are presented in this paper.

2. Results and discussion

The synthesis of the 4-quinolinoacetamide and 4-quinolinoben-

zamide urea derivatives is outlined in Scheme 1. The starting sub-

strate 2-methyl-6-nitro-4-aminoquinoline (1) was prepared via a

known strategy.⁴The reaction of 1 with acetyl chloride, benzoyl

chloride, substituted benzoyl chloride or chloroacetyl chloride fur-

nished the required amides 2–7. These amides were subjected to

reduction either via hydrogenation in the presence of Pd-C for

* Corresponding author. Tel.: +91 522 2621411 18x4368; fax: +91 522 2623405.

E-mail addresses: batra_san@yahoo.co.uk, s_batra@cdri.res.in (S. Batra).

doi:10.1016/j.bmc.2008.11.021

204

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

OMe

NH

H

OMe

H

O

N

H₂N

NH₂

N

H

N

OMe

F

O

H

R²

O

R¹

R³

Me

H₂N

H

O

S

O

S

N

H

N

F

O

R⁴

O

H

N

H

N

O O

O

Fe

O

HN

O

N

Cl

NRR¹

Figure 1. A few urea derivatives which display antimalarial activity.

NH₂

O₂N

CN

O

O₂N

i

ii

+

NH₂

N

1

O

HN

R

HN

N

R

H

N

R¹

H

HN

N

R

N

iv

O₂N

H₂N

iii

O

N

13

a-o

14a-o

8-12

2 R= Ph

2-7

15a-g,i-o

3 R= 2-Cl-C₆H₄

4 R= 3-Cl-C₆H₄

5 R= 2-furyl

6 R= Me

16a,c,f,h,j,l-m

17

a,h,j,m

v

O

R²

7 R=CH₂Cl

HN

N

H

N

HN

N

R²

HN

R²

N

iv

iii

R¹

O₂N

H₂N

O

24a-m,n-o

25g,j,l,m

a,g,i,l,m,o

N

18-20

26

21-23

18, 21, 24 R²=

H₂C

N

NMe

19, 22, 23 R²= H₂C

N

NEt

20, 23, 26 R²=

H₂C

Scheme 1. Reagents and conditions: (i) SnCl₄, toluene, reﬂux, 4 h; (ii) RCOCl, Et₃N, DMAP, CH₂Cl₂, rt, 8–10 h; (iii) Pd-C (10%), MeOH, rt, 1 h or SnCl₂, MeOH, reﬂux, 1 h; (iv) R¹-

C₆H₄-NCO, MeCN, rt, 2 min to 10 h; (v) N-methyl piperazine or N-ethyl piperazine or piperidine, DMF, rt, 2–3 h.

2,5–6 to furnish 8,11–12 or in the presence of SnCl₂ꢀ2H₂O for 3–4

to yield 9–10 in good yields. The latter route was adopted to cir-

cumvent dehalogenation of the aromatic ring which generally

takes place under catalytic-hydrogenation.⁵With the required

amines in hand two well known strategies were employed to

obtain the urea derivatives 13–14a–o, 15a–g,i–o, 16a,c,f,h,j,l–o

and 17a,h,j,m. The ﬁrst route involved the reaction of amine with

a commercially available isocyanate in acetonitrile whereas the

second one involved the activation of an amine with p-nitrobenzyl-

chloroformate and its treatment with the 6-amino-2-methyl-

4-quinolinamide to afford the ﬁnal compound in moderate to

excellent yields. With the objective to introduce diversity at the

4-position compound 7 was further treated with substituted

piperazines and piperidine to furnish products 18–20. Reduction

of the nitro-group in 18–20 yielded the respective amino deriva-

tives 21–23. These amines were utilized to synthesize the urea

derivatives 24a–m,n–o, 25g,j,l,m, 26a,g,i,l,m,o using the above

mentioned procedures.

2.1. In vitro antimalarial activity

The results of the in vitro antimalarial assay of 80 analogs

against 3D7 chloroquine-sensitive P. falciparum strain are shown

in Table 1. As noted above the present study evolved as a conse-

quence of the literature precedence that urea pharmacophore

show hydrogen bonding with the aspartic acid 154 of the PfDHFR.

The quinoline as the basic core was selected due to its presence in

several compounds being used as antimalarial in clinics. The MICs

(lg/mL) for all compounds were initially recorded and the analogs

displaying an MIC of 0.5 g/mL or less were subjected to IC₅₀eval-

l

Table 1

Results of in vitro and in vivo antimalarial assays of compounds

Compound

R (13–17)/R²(24–26)

R¹

MIC (l

g/mL)

IC₅₀(ng/mL)

Selectivity index (SI)

In vivo (% mean parasitemia SD on day 4)

In vivo (% mean parasitemia SD on day 7)

13a

13b

13c

13d

13e

13f

13g

13h

13i

Ph

4-Cl

4-F

4-Br

3-Cl

3-F

3-CN

3-CF₃

4-COMe

3-COMe

3-Cl-4-Me

3-Cl-2-Me

3,4-Cl₂

3,5-Cl₂

3-Cl-4-F

4-Cl-3-CF₃

4-Cl

4-F

4-Br

3-Cl

3-F

>50

10

50

10

50

10

2

50

1

2

10

1

2

50

2

0.5

2

1

2

1

10

1

—

10.9

—

19.4

—

219.6

—

28.4

—

44.5

—

194.4

21.7

—

35.6

14.4

—

9.9

—

34.0

—

218.1

68.2

—

13j

13k

13l

13m

13n

13o

14a

14b

14c

14d

14e

14f

14g

14h

14i

14j

14k

14l

14m

14n

14o

15a

15b

15c

15d

15e

15f

15g

15i

15j

15k

15l

15m

15n

15o

16a

16c

16f

16h

16j

16l

16m

16o

17a

17h

17j

2-Cl-C₆H₄

3-Cl-C₆H₄

2-furyl

Me

—

32.1

—

2401.9

—

1.90 0.55

4.23 3.31

—

6.05 3.05

—

3.03 0.67

—

2.15 0.47

—

57.6

—

8.80 3.26

9.77 2.64

—

12.11 9.35

—

5.98 1.08

—

5.08 0.40

—

3-CN

3-CF₃

4-COMe

3-COMe

3-Cl-4-Me

3-Cl-2-Me

3,4-Cl₂

3,5-Cl₂

3-Cl-4-F

4-Cl-3-CF₃

4-Cl

4-F

4-Br

3-Cl

3-F

—

205.1

—

16.8

505.0

—

270.9

—

6014.2

—

184.5

—

187.7

125.6

—

3909.5

1547.0

—

524.7

—

2

10

—

1

10

2

50

>50

1

3-CN

3-CF₃

2

3-COMe

3,5-Cl₂

3-Cl-4-Me

3-Cl-2-Me

3,4-Cl₂

3-Cl-4-F

4-Cl-3-CF₃

4-Cl

10

1

10

2

0.5

>10

0.5

1

0.5

10

0.5

Insoluble

2

—

10

50

—

3.76 2.85

—

2.95 2.02

15.5 7.98

—

13.2 11.7

—

1.84 3.67

—

21.1 7.75

—

13.9

57.1

0.4

—

134.6

—

9.9

—

4-Br

3-CN

—

0.0 0.0^*

4-COMe

3-Cl-4-Me

3,4-Cl₂

3,5-Cl₂

4-Cl-3-CF₃

4-Cl

—

0.61 1.29

—

713.3

—

Me

4-COMe

3,5-Cl₂

—

(continued on next page)

Table 1 (continued)

Compound

R (13–17)/R²(24–26)

R¹

MIC (

lg/mL)

IC₅₀(ng/mL)

—

Selectivity index (SI)

—

In vivo (% mean parasitemia SD on day 4)

—

In vivo (% mean parasitemia SD on day 7)

—

17m

Me

3-Cl-4-Me

2

24a

24b

24c

24d

24e

24f

4-Cl

0.5

2

5.0

—

N

H₂C

Me

Et

4-F

—

H₂C

4-Br

1

—

3-Cl

0.25

10

13.0

—

549.7

—

18.8 6.53^*

50.0 0.0

3-F

—

3-CN

2

—

24g

24h

24i

3-CF₃

0.25

1

0.8

14.0

146.3

3.3

—

2594.9

—

2.5 1.94

21.9 10.9

4-COMe

3-COMe

3-Cl-4-Me

3-Cl-2-Me

3,4-Cl₂

3,5-Cl₂

4-Cl-3-CF₃

3-CF₃

—

0.5

0.25

>10

0.25

0.5

2

524.5

—

24j

1.67 1.76

5.15 1.19

24k

24l

—

2.2

0.4

18.2

28.0

3.5

—

2.55 1.53

1.50 1.47

24m

24o

25g

25j

4404.8

53.4

—

4.78 2.30

15.5 2.87

2.28 2.02

11.0 6.21

—

Et

3-Cl-4-Me

3,4-Cl₂

3,5-Cl₂

4-Cl

—

Et

25l

—

Et

25m

26a

2

—

0.5

23.0

64.9

N

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

207

uation and cytotoxicity assay. Index of selectivity (SI) indicates

comparative safety of compounds against the parasites. Finally

several analogs were randomly selected for the in vivo evaluation

against mdr P. yoelii nigeriensis or CQ-resistant P. yoelii. The MIC

and IC₅₀of CQ that was used as standard in the bioassay were re-

corded as 15.0 ng/mL and 2.0 ng/mL, respectively. Notably, com-

pounds 8–12 and 21–23 had MIC value of more than 50 (lg/mL)

reﬂecting that the activity of these compounds is essentially due

to the presence of urea unit. Broadly the urea derivatives described

herein can be divided in two broad structural variant. The ﬁrst

being the 2-methyl-6-ureido-4-quinolinobenzamide derivatives

(13–16) while the later being the 2-methyl-6-ureido-4-quin-

olinoacetamide derivatives (17,24–26). For compounds belonging

to benzamide group it was observed that analogs (13a–o) bearing

unsubstituted phenyl carbamoyl moiety at 4-position did not elicit

good biological response. Only two compounds 13l and 13o carry-

ing 3,4-Cl₂and 4-Cl-3-CF₃substitutions, respectively were found to

show activity at 1.0

compared to 19.38 ng/mL for 13o. The other two analogs to show

modest effect included 13j and 13m with MIC value of 2.0 g/

lg/mL although 13l had IC₅₀of 10.94 ng/mL as

l

mL. Analysis of the activity pattern of compounds within this

group revealed that except for 13k and 13n, compounds having

disubstitution on the phenyl ring of the aryl urea subunit displayed

better antimalarial effect in comparison to compounds containing

monosubstituted phenyl ring.

The introduction of a chloro-group at 2-position of the phenyl

ring of the benzamide subunit resulting in 14 signiﬁcantly im-

proves upon the antimalarial effect. Out of 14a–o except for 14b,

14k and 14n all compounds displayed potent bioactivity with

MIC of 2.0

with a value of 0.5

ever calculation of the IC₅₀s of all compounds showing MIC of

1.0 g/mL delineated that 14m containing 3,5-Cl₂as the substitu-

l

g/mL or below. On the basis of MIC compound 14d

lg/mL displayed most signiﬁcant activity. How-

l

tion on the phenyl ring of the urea unit was more potent with a va-

lue of 21.0 ng/mL. Compound 14f bearing nitrile-group at 3-

position was slightly less active with IC₅₀of 28.1 ng/mL whereas

14o had a value of 35.6 ng/mL. However SI of 14f was fourfold bet-

ter as compared to 14 m. Unfortunately 14d which had better MIC

seems to be less potent on the basis of the IC₅₀with a value of

219.6 ng/mL. Even the SI of this compound was found to be low

indicating it to be less safe as compared to 14f,m or o.

Next modifying the point of substitution of the chloro group in

the phenyl ring of the benzamide subunit from 2- to 3-position in

the next group of compounds (15) seems to have altering effect on

the bioactivity. Although no clear pattern emerged, it was observed

that compounds comprising of chloro-substitution on the phenyl

ring of the urea unit display better activity. Compounds 15a, 15k

and 15n having 4-Cl, 3-Cl-4-Me and 3-Cl-4-F group, respectively,

had MIC of 1.0

lg/mL. Compound 15g having 3-CF₃too was found

to have MIC of 1.0

l

g/mL. However on the basis of IC₅₀value of

these compounds, 15g with a value of 9.9 ng/mL followed by 15a

with a value of 14.4 ng/mL were best amongst this series. The high

SI of 15g indicated it to be safe too.

In subsequent set of compounds (16) the phenyl group of the

benzamide moiety was replaced with a furyl ring. Interestingly

for this prototype structure a set of only eight compounds were

prepared incorporating only those substitutions in the phenyl ring

of the urea group which have shown good activity for 13–15. Out

of these compounds, 16l could not be evaluated as it was found

to be insoluble while all other analogs displayed promising activity

except for 16h. On the basis of the MIC 16a, 16f and 16j containing

4-Cl, 3-CN and 3-Cl-4-Me, respectively, on the phenyl ring of urea

subunit were observed to be equipotent with a value of 0.5

lg/mL

whereas 16o with 4-Cl-3-CF₃had MIC of 0.25 g/mL. Examination

l

of IC₅₀however resulted in a lower value for 16f (0.4 ng/mL) than

16o (9.9 ng/mL) or 16a (13.9 ng/mL) or 16j (134.6 ng/mL). Hence

208

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

on the basis of these results it was evident that compound 16f was

ﬁvefold more potent as compared to the standard CQ used in the

assay. The high SI value indicated that compounds belonging to

this prototype would be less toxic.

In the next phase of the study the urea derivatives comprising

of acetamide or substituted acetamide group at 4-position of the

quinoline ring were investigated. The examination of four analogs

(17a,h,j,k) comprising of unsubstituted acetamide group did not

show any promising activity therefore no more compounds

belonging to the prototype were pursued. As indicated in the pre-

ceding text the synthesis of substituted acetamide urea derivative

was accomplished by introducing the chloroacetyl group and then

replacing the chloro group with secondary amines including

substituted piperazines and piperidine. This exercise ensued from

the fact that several piperazine derivatives have been reported to

display signiﬁcant antimalarial effect.⁶In the ﬁrst set of com-

pounds N-methylpiperazine was introduced to prepare 24a–o. It

was pleasing to note that except for compounds 24e and 24k all

compounds had MIC of 2.0 lg/mL or less. The IC₅₀evaluation of

compounds revealed 24g (0.79 ng/mL) and 24m (0.42 ng/mL) to

be even more potent than CQ (2.0 ng/mL) whereas 24l (2.19 ng/

mL) displayed almost similar antimalarial effect to that of CQ. Even

compounds 24d and 24h were signiﬁcantly potent with IC₅₀of

13.0 ng/mL and 14.0 ng/mL whereas 24o had IC₅₀value of

18.2 ng/mL. The SI values for 24g and m revealed them to be

non-toxic.

Figure 2B. Structure of WR99210 and its docked conformation of in yellow. Crystal

structure conformation of WR99210 (blue) in the pfDHFR.

Replacing the methyl with ethyl as in compounds 25g,j,l,m

however, lowered the activity. Compared to the methyl analogs

Leu46, Trp48, Lys49, Phe58, Pro113, Phe116, Leu119, Arg122,

Tyr170 and Phe223 (Fig. 2B). In all cases, Leu46, Phe58, Ile164

and Phe223 are predicted to exhibit major hydrophobic contacts

with the 2-methyl-quinoline core inside the inhibitor binding site.

As seen from the docking studies, the 2-methyl-quinoline core act

the corresponding ethyl analogs were twice less active. The IC₅₀

of two compounds 25l (3,4-Cl₂) and 25m (3,5-Cl₂) having MIC of

0.5 g/mL were observed to be 28.0 ng/mL and 3.5 ng/mL,

s

l

respectively.

as possible basic and

p-donor site and is involved in edge to face

In the last group of compounds (26a,g,i,l,m,o) the piperazine

group was replaced by piperidine unit. Although only 6 com-

pounds were synthesized and evaluated in this group, except 26i,

p–p

stacking interaction with the nicotinamide ring of NADPH.

This edge to face or T shaped aromatic stacking interaction is very

important for pfDHFR inhibition and is responsible for the stability

of the protein–ligand complex.

all compounds show promising activity with MIC of 0.5 lg/mL or

less. This led to the IC₅₀evaluation of all compounds from the

group and based on it 26a, bearing chloro at 4-position of the phe-

nyl ring, with a value of 23.0 ng/mL was discovered to be the most

active. The IC₅₀value for 26m and 26o were observed to be

28.8 ng/mL and 35.8 ng/mL, respectively. However as compared

to compounds belonging to type 24 these compounds had low SI

indicating to be relatively more toxic as compared to 24.

The phenyl moiety of the urea subunit make lipophilic interac-

tions with Pro 113 and Phe 116 and it extends towards the solvent

(as revealed from the docked conformations) so there is only small

substituent effect on the inhibitory potency. Instead the substitu-

2.2. Docking studies

Molecular docking studies of 2-methyl-6-ureido-4-quinolina-

mides into pfDHFR binding site revealed very clear preference for

the inhibitor binding pocket and all the compounds occupy the

same spatial position as the co-crystallized pfDHFR inhibitor

WR99210 (Fig. 2A). Most of the 2-methyl-6-ureido-4-quinolina-

mides bind in more or less similar fashion with its 2-methyl quin-

oline ring occupying the interior of the deep cleft and its phenyl

substitution towards urea is extended to the entrance of the hydro-

phobic binding cavity. The 2-methyl quinoline core of the com-

pounds was held in the pocket by combination of van der Waals

and hydrophobic interactions with the protein. The most impor-

tant pfDHFR–ligand interactions involve residues Ile14, Leu40,

Figure 3. Docked conformation of 24g (red) 24l (yellow) 25g (blue) 26g (orange) in

the pfDHFR.

Figure 2A. Structure of WR99210.

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

209

ents at 4-position of the 2-methyl quinoline ring have signiﬁcant

effect on the inhibitory potency. To facilitate the analysis of the

biological data, 2-methyl-6-ureido-4-quinolinamides are classiﬁed

according to the substitution at 4-position of the 2-methyl-quino-

line ring and the nature of the substituent. As seen from our dock-

ing conformations bulkier substituents are preferred at this

position due the hydrophobic environment provided by the side

chains of Ile14, Leu46, Phe58, Ile164 and Phe223. Compounds of

series 24, 25 and 26 bearing methyl piperazine, ethyl piperazine

and piperidine substituents, respectively displayed a binding mode

as exempliﬁed by representative compounds 24g, 24l, 25g and 26g

in Figure 3. These compounds show hydrophobic interactions with

Ile 14, Leu 40, Leu 46, Phe 58, Ile 174, Tyr 170 and Phe 223.

In addition to these hydrophobic interactions, CH-

are also found to occur between the system of Phe58 and the CH

in methyl piperazine, ethyl piperazine and piperidine ring. It is

hypothesized that the presence of this particular CH- interaction

is responsible for the optimal orientation of the 2-methyl-quino-

line core to make -stacking interaction with the nicotinamide ring

p interactions

p

of NADPH. Any replacement of these groups with a smaller group

led to decrease in the inhibitory activity. The displacement of this

piperazine and piperidine moiety with phenyl, 2 and 3 chloro

substituted phenyl ring in compounds 13a–o, 14a–o and 15a–o,

respectively, led to decrease in the inhibitory activity where

replacement causes the decrease in the hydrophobic interactions

and thus decrease in the net hydrophobicity lower down the inhib-

itory potencies. In contrast although the series 16a,c,f,h,j,l–o bear-

ing furan ring show similar proﬁle, they display better antimalarial

effect. In case, compound 13i, 14j, 15a and 16e were not able to as-

sume a conformation exactly similar to that of the active com-

pounds because of their enhanced conformational rigidity due to

the presence of planar substituents at 4-position (Fig. 4). However

the docking studies performed in this study could not explain the

pronounced activity of ureides with furan moiety.

Figure 5. Docked conformation of 17h (magenta), 17j (brown) in the pfDHFR.

2.3. In vivo antimalarial activity

Three compounds namely 16f, 24d and 26o were evaluated at

an oral dose of 100 mg/kg/day ꢁ 4 days against mdr P. yoelii nige-

riensis whereas rests of evaluations were performed at 50 mg/kg/

day ꢁ 4 days against CQ-resistant P. yoelli N67. Only one group of

animals treated with compound 16f, no parasitemia was observed

on day 4 though low level of recrudescence occurred on day 7.

However as compared to control group of untreated animals this

activity was promising as indicated by 100% and 91.29% inhibition

on days 4 and 7, respectively. Another group of animals treated

with compound 26o also showed marked effect on day 4 which

diminished by day 7. Among the several sets of animals which

were treated with the compounds at an oral dose of 50 mg/kg/

day ꢁ 4 days schedule elicited only modest suppression of parasi-

temia. The group of animals treated with 16j showed signiﬁcant

initial suppression but was almost inactive by day 7. On the other

hand in the group of animals treated with 24l, there was only a

moderate increase in the levels of parasitemia even after day 7

illustrating its better antimalarial effect, that is, 92.9% inhibition

on day 7. However since in most of the treated animals some level

of parasitemeia was observed it was concluded that none of the

compound had good in vivo antimalarial activity. Several reasons

could be assigned for the low in vivo effect. The in vitro effect

was investigated in the CQ-sensitive P. falciparum but the in vivo

effect was examined in either mdr P. yoelii nigeriensis or CQ-resis-

tant P. yoelii. Due to absence of CQ-resistant P. falciparum strain at

this place we were unable to assess the activity of these com-

pounds against it. Secondly poor solubility of these urea deriva-

tives could have led to improper absorption and metabolism in

the biosystem.

Further analysis of docking results revealed that compounds

(17a,h,j,m) substituted with acetamide group at 4-position of the

quinoline ring were devoid of any CH-

p hydrogen bonds with

Phe 58, hence 2-methyl quinoline ring was not able to attain prop-

er conformation to make T shaped stacking (Fig. 5) and therefore

the compounds were almost inactive.

2.4. Antibacterial activity

Five strains of bacteria (Streptococcus faecalis, Klebsiella pneumo-

niae, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus

aureus), including Gram +ve and Gram –ve were included for the

bioassay. Compounds which showed MIC of >50

lg/mL or above

have not been included for the discussion. It was interesting to

note that though several compounds show activity in different

Figure 4. Docked conformation of 13i (violet), 14j (light green), 15a (grey), 16e

(light blue) in the pfDHFR.

210

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

Table 2

that the in vivo effect may have been inﬂuenced by the lower

Antibacterial activity of selected compounds only

absorption of these compounds. Nevertheless, the compounds con-

taining urea group does provide impetus to incorporate this group

in other heterocyclic systems and evaluate their antimalarial effect.

Compound

Bacteria^aMIC (

lg/mL)

1

2

3

4

5

13m

15a

24c

24j

24l

24m

24o

25l

25m

Gentamicin

0.01

12.5

6.25

ND

1.56

3.125

3.1

ND

0.78

0.04

6.25

12.5

1.56

12.5

6.25

0.78

0.0025

12.5

6.25

1.56

ND

12.5

>50

ND

0.09

3.12

ND

25

6.25

ND

6.25

3.12

6.25

4. Experimental

4.1. General

Melting points are uncorrected and were determined in capil-

lary tubes on an apparatus containing silicon oil. IR spectra were

recorded using a Perkin-Elmer’s Spectrum RX I FTIR spectropho-

tometer. ¹H NMR and ¹³C NMR spectra were recorded either on a

Bruker DPX-200 FT or Bruker Avance DRX-300 spectrometer, using

TMS as an internal standard (chemical shifts in d). The ESMS and

FABMS were recorded on MICROMASS Quadro-II LCMS and JEOL

SX/102/DA 6000 system, respectively. Elemental analyses were

performed on a Carlo Erba’s 108 or an Elementar’s Vario EL III

microanalyzer.

ND

0.18

ND

25

a

1. S. faecalis, 2. K. pneumoniae, 3. E. coli, 4. P. Aeruginosa, 5. S. Aureus.

strains of bacteria only compounds 13m and 15a were found to be

active against P. aeruginosa which is a Gram –ve strain of bacteria.

Compounds 13m, 15a, 24j, 24l, 24m, 24o, 24c, 25l, and 25m dis-

played MICs of 1.56–25

(Table 2).

lg/mL against other four strains of bacteria

Based on the MIC values against different strains of bacteria

compound 13m was found to be a potent antibacterial. The values

4.1.1. General procedure for the preparation of N-(2-methyl-6-

nitroquinolin-4-yl)carbamides (2–7)

of 0.01

0.0025

l

g/mL against S. faecalis, 0.04

g/mL against E. coli and 0.09

l

g/mL against K. pneumoniae,

g/mL against S. aureus were

To a mixture of Et₃N (22.2 mmol, 3.2 mL), DMAP (1.4 mmol,

0.17.g) and 2-methyl-6-nitroquinolin-4-amine (1) (14.8 mmol,

3.0 g) in anhydrous CH₂Cl₂(50 mL), was added dropwise an appro-

priate acid chloride (22.16 mmol) under stirring at 0 °C. The reac-

tion mixture was allowed to warm up to the room temperature

and further stirred for 4 h. The precipitated solid was ﬁltered, dried

and crystallized from MeOH to furnish N-(2-methyl-6-nitroquino-

lin-4-yl)-carbamides (2–7) as crystalline solid in good yields.

best amongst all the compounds screened and were even better

than the standard drug gentamicin by many folds. But its MIC

against P. aeruginosa which was observed to be 12.5

only twofold better than gentamicin. Compound 24l showed MIC

of 1.56 g/mL against the S. faecalis whereas compounds 24m

lg/mL was

l

and 24o were twofold less active against the same strain but these

compounds were less active than the standard drug.

Other compounds were found to be active at MIC of 6.25

or more. However against the K. pneumoniae compounds 24l, 24m

and 24o were equipotent with MIC of 1.56 g/mL whereas 24c

showed modest activity with MIC of 6.25 g/mL. Compounds 24l,

24m and 24o had similar activity against E. coli with MIC of

1.56 g/mL. Against the S. aureus though none of the compound

showed comparable activity to the one elicited by 13m, compound

14j had the MIC of 3.12 g/mL. On the other hand compounds 24l,

24o and 25l were twofold less active with the MIC of 6.25 g/mL.

lg/mL

4.1.1.1. N-(2-Methyl-6-nitroquinolin-4-yl)benzamide (2). 87%

as a yellow solid, mp 248–249 °C; m_max(KBr) 1698 (CO), 3276

(NH) cm^ꢂ^{1 1}H NMR (CDCl₃, 200 MHz) d = 2.83 (s, 3H, CH₃), 7.59–

;

l

7.70 (m, 3 H, ArH), 8.02 (dd, 2H, J₁= 1.2 Hz, J₂= 7.6 Hz, ArH), 8.18

(d, 1H, J = 9.2 Hz, ArH), 8.46–8.52 (m, 2H, ArH), 8.65 (s, 1H, NH),

8.86 (d, 1H, J = 2.2 Hz, ArH); mass (ES+) m/z = 308.0 (M⁺+1). Anal.

Calcd for C₁₇H₁₃N₃O₃C, 66.44; H, 4.26; N, 13.67. Found C, 66.73;

H, 4.06; N, 13.82.

l

Analysis of the SAR of the active derivatives clearly demonstrate

that a chloro group at 3-position of the phenyl ring of the aryl urea

subunit is strongly required for compounds to show antibacterial

activity.

4.1.1.2. 2-Chloro-N-(2-methyl-6-nitroquinolin-4-yl)benzamide

(3). 87% as a light yellow solid, mp 192–194 °C;

m_max(KBr) 1668

(CO), 3236 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.73 (s,

;

3H, CH₃), 7.54–7.67 (m, 3H, ArH), 7.73 (dd, 1H, J₁= 1.7 Hz, J₂= 7.1

Hz, ArH), 8.10 (d, 1H, J = 9.2 Hz, ArH), 8.26 (s, 1H, ArH), 8.43 (dd,

1H, J₁= 2.5 Hz, J₂= 9.2 Hz, ArH), 9.40 (d, 1H, J = 2.4 Hz, ArH),

11.26 (s, 1H, NH); mass (ES+) m/z = 342.1 (M⁺+1), 344.0 (M⁺+3).

Anal. Calcd for C₁₇H₁₂ClN₃O₃C, 59.75; H, 3.54; N, 12.30. Found C,

59.98; H, 3.45; N, 12.62.

3. Conclusions

In summary, we have disclosed the antimalarial activity of a

new series of urea derivatives. On the basis of the compounds stud-

ied in the present study it is indicated that derivatives comprising

of phenyl ring of the aryl urea subunit bearing disubstitutions at 3-

and 4-positions elicit better biological activity. Amongst these di-

substitutions the chloro group was the most favored. On the other

hand the amido group present at the 4-position of the quinoline

incorporating the N-methyl piperazine or the piperidine ring were

best suited for the antimalarial activity. Introduction of benzam-

ides generally leads to decrease in activity although the 2-chloro-

phenyl containing benzamides displayed better antimalarial

activity as compared to unsubstituted phenyl group. In contrast

the replacement of phenyl with furan moiety yielded compounds

with good antimalarial effect. Although the docking studies of

these compounds with the pfDHFR were accomplished, in the ab-

sence of investigation in a bioassay against DHFR it is premature

to comment on the possible mode of action of these compounds.

The lack of complete suppression of parasitemia, however, reﬂects

4.1.1.3. 3-Chloro-N-(2-methyl-6-nitroquinolin-4-yl)benzamide

(4). 89% as an off white solid, mp 201–203 °C;

m_max(KBr) 1685 (CO),

3219 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.71 (s, 3H,

;

CH₃), 7.64 (t, 1H, J = 7.9 Hz, ArH), 7.75 (d, 1H, J = 8.6 Hz, ArH),

7.99 (d, 1H, J = 7.7 Hz, ArH), 8.04 (s, 1H, ArH), 8.09–8.12 (m, 2H,

ArH), 8.44 (dd, 1H, J₁= 2.4 Hz, J₂= 9.2 Hz, ArH), 9.25 (d, 1H,

J = 2.4 Hz, ArH), 11.00 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz)

d = 25.1, 116.7, 119.9, 121.3, 123.3, 127.5, 128.5, 131.0, 132.5,

133.7, 136.6, 144.1, 144.4, 151.0, 164.0, 166.2; mass (ES+) m/

z = 342.2 (M⁺+1), 344.1 (M⁺+3). Anal. Calcd for C₁₇H₁₂ClN₃O₃C,

59.75; H, 3.54; N, 12.30. Found C, 59.51; H, 3.83; N, 12.17.

4.1.1.4. N-(2-Methyl-6-nitroquinolin-4-yl)-2-furamide (5). 84%

as a white solid, mp 232–234 °C; m_max(KBr) 1672 (CO), 3325

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.82 (s, 3H, CH₃),

;

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

211

6.70 (q, 1H, J = 1.7 Hz, ArH), 7.43 (d, 1H, J = 3.6 Hz, ArH), 7.73 (d, 1H,

J = 1.1 Hz, ArH), 8.18 (d, 1H, J = 9.2 Hz, ArH), 8.49–8.53 (m, 2H,

ArH), 8.88–8.91 (m, 2H, ArH and NH); mass (ES+) m/z = 298.2

(M⁺+1). Anal. Calcd for C₁₅H₁₁N₃O₄C, 60.61; H, 3.73; N, 14.14.

Found C, 60.84; H, 4.01; N, 14.23.

1.65 (m, 2H, CH₂), 1.83–1.90 (m, 4H, 2ꢁ CH₂), 2.71–2.74 (m, 4 H,

2ꢁ CH₂), 2.79 (s, 3H, CH₃), 3.27 (s, 2H, CH₂), 8.14 (d, 1H, J = 9.3 Hz,

ArH), 8.45–8.50 (m, 2H, ArH), 8.92 (d, 1H, J = 2.4 Hz, ArH), 11.01

(s, 1H, NH); ¹³C NMR (CDCl₃, 50 MHz) d = 23.9, 26.6, 27.1, 55.5,

63.3, 111.5, 117.0, 117.7, 123.2, 131.7, 141.9, 144.9, 151.0, 165.3,

170.3; mass (ES+) m/z = 329.1 (M⁺+1). Anal. Calcd for C₁₇H₂₀N₄O₃

C, 62.18; H, 6.14; N, 17.06. Found C, 62.33; H, 5.96; N, 17.26.

4.1.1.5. N-(2-Methyl-6-nitroquinolin-4-yl)acetamide (6). 91%

as a light yellow solid, mp 210–215 °C; m_max(KBr) 1680 (CO),

3263 (NH) cm^ꢂ1

;

¹H NMR (DMSO-d₆, 300 MHz) d = 2.42 (s, 3H,

4.1.3. General procedure for the preparation of N-(6-amino-2-

methylquinolin-4-yl)-carbamides (8, 11–12, 21–23)

CH₃), 2.87 (s, 3H, CH₃), 8.42 (d, 1H, J = 9.3 Hz, ArH), 8.56 (s, 1H,

ArH), 8.69 (dd, 1H, J₁= 2.1 Hz, J₂= 9.3 Hz, ArH), 9.75 (d, 2H,

J = 2.0 Hz, ArH), 11.19 (s, 1H, NH); mass (ES+) m/z = 246.0 (M⁺+1).

Anal. Calcd for C₁₂H₁₁N₃O₃C, 58.77; H, 4.52; N, 17.13. Found C,

59.06; H, 4.31; N, 17.40.

To a solution of appropriate N-(2-methyl-6-nitroquinolin-4-

yl)carbamide (2, 5–6, 18–20) (4.1 mmol) was added 10% Pd-C

(0.20 g) under nitrogen atmosphere. Thereafter, the atmosphere

of the vessel was replaced by hydrogen gas and reaction was car-

ried out on the Parr assembly at 40 psi at room temperature for

1 h. The catalyst was then ﬁltered over a celite bed and the ﬁltrate

was evaporated on rotavapour under reduced pressure to yield a

residue. The residue was puriﬁed by recrystallization or column

chromatography over silica gel using hexanes/EtOAc (65-55:35-

45, v/v) as the eluent to yield compounds 8, 11–12, 21–23.

4.1.1.6. 2-Chloro-N-(2-methyl-6-nitroquinolin-4-yl)acetamide

(7). 80% as an off white solid, mp 153–155 °C; m_max(KBr) 1676

(CO), 3255 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.68 (s,

;

3H, CH₃), 4.59 (s, 2H, CH₂), 8.07 (d, 1H, J = 9.2 Hz, ArH), 8.19 (s,

1H, ArH), 8.43 (dd, 1H, J₁= 2.5 Hz, J₂= 9.2 Hz, ArH), 9.38 (d, 2H,

J = 2.3 Hz, ArH), 11.19 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz)

d = 25.0, 43.2, 112.6, 117.3, 119.1, 122.3, 130.0, 142.3, 143.5,

149.8, 163.2, 165.9; mass (ES+) m/z = 280.1 (M⁺+1), 282.1 (M⁺+3).

Anal. Calcd for C₁₂H₁₀ClN₃O₃C, 51.53; H, 3.60; N, 15.02. Found C,

51.68; H, 3.92; N, 14.80.

4.1.3.1. N-(6-Amino-2-methylquinolin-4-yl)benzamide (8). 85%

as a light yellow solid, mp 160–162 °C; m_max(KBr) 1698 (CO),

3367 (NH and NH₂) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.81

;

(s, 3H, CH₃), 6.25 (br s, 2 H, NH₂), 7.31 (d, 1H, J = 1.7 Hz, ArH),

7.45 (dd, 1H, J₁= 1.8 Hz, J₂= 9.0 Hz, ArH), 7.58–7.63 (m, 2H, ArH),

7.67–7.72 (m, 1H, ArH), 8.04–8.11 (m, 3H, ArH), 8.18 (s, 1H, ArH),

10.93 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 21.7, 100.0,

115.0, 121.9, 122.3, 127.3, 127.7, 128.4, 129.9, 131.4, 132.1,

133.1, 141.3, 146.4, 150.7, 165.4, 166.6; mass (ES+) m/z = 278.3

(M⁺+1). Anal. Calcd for C₁₇H₁₅N₃O C, 73.63; H, 5.45; N, 15.15.

Found C, 73.90; H, 5.69; N, 15.01.

4.1.2. General procedure for the preparation of N-(2-methyl-6-

nitroquinolin-4-yl)-2-(substituted amino)acetamide (18–20)

To a suspension of secondary amine (13.8 mmol) and NaH

(28.6 mmol, 0.69 g) in 15 mL of anhydrous DMF was added a solu-

tion of 2-chloro-N-(2-methyl-6-nitroquinolin-4-yl)acetamide (7)

(11.5 mmol, 3.2 g) in anhydrous DMF at 0 °C under nitrogen atmo-

sphere. The reaction mixture was stirred for 6–10 h at room tem-

perature. On completion, the reaction mixture was poured into

ice cold water and allowed to warm up to ambient temperature.

The mixture was extracted with EtOAc (3ꢁ 50 mL). The combined

organic layer was washed with brine (60 mL) and dried over anhy-

drous Na₂SO₄and evaporated under reduced pressure to obtain a

residue. The puriﬁcation via silica gel column chromatography

using hexanes/EtOAc (20-50:50-80, v/v) as the mobile phase

yielded the desired carbamides (18–20).

4.1.3.2. N-(6-Amino-2-methylquinolin-4-yl)-2-furamide (11). 87%

as a light yellow silod, mp 195–197 °C; m_max(KBr) 1665 (CO),

3327 (NH and NH₂) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.82

;

(s, 3H, CH₃), 6.70 (q, 1H, J = 1.7 Hz, ArH), 7.43 (d, 1H, J = 3.6 Hz,

ArH), 7.73 (d, 1H, J = 1.1 Hz, ArH), 8.18 (d, 1H, J = 9.2 Hz, ArH),

8.49–8.53 (m, 2H, ArH), 8.88–8.91 (m, 2H, ArH and NH); mass

(ES+) m/z = 268.2 (M⁺+1). Anal. Calcd for C₁₅H₁₃N₃O₂C, 67.40; H,

4.90; N, 15.72. Found C, 67.04; H, 4.96; N, 15.65.

4.1.2.1. N-(2-Methyl-6-nitroquinolin-4-yl)-2-(4-methylpipera-

4.1.3.3. N-(6-Amino-2-methylquinolin-4-yl)acetamide (12). 83%

as a yellow solid, mp 280–282 °C; m_max(KBr) 1680 (CO), 3456

zin-1-yl)acetamide (18).

75% as a white solid, mp 245–

247 °C; m_max(KBr) 1691 (CO), 3405 (NH) cm^ꢂ1

;

¹H NMR (CDCl₃,

(NH and NH₂) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.32 (s,

;

300 MHz) d = 2.46 (s, 3H, CH₃), 2.74–2.84 (m, 11H, CH₃and 4ꢁ

CH₂), 3.34 (s, 2H, CH2), 8.15 (d, 1H, J = 9.2 Hz, ArH), 8.47–8.51

(m, 2H, ArH), 8.93 (d, 2H, J = 2.3 Hz, ArH), 10.89 (s, 1H, NH); mass

(ES+) m/z = 344.1 (M⁺+1). Anal. Calcd for C₁₇H₂₁N₅O₃: C, 59.46; H,

6.16; N, 20.40. Found C, 59.74; H, 5.97; N, 20.59.

3H, CH₃), 2.71 (s, 3H, CH₃), 7.34–7.39 (m, 2H, ArH), 7.91 (d, 1H,

J = 8.9 Hz, ArH), 8.17 (s, 1H, ArH), 10.51 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 75 MHz) d = 19.9, 23.9, 99.7, 110.5, 120.2, 121.9,

123.5, 132.6, 144.4, 147.7, 150.1, 170.0; mass (ES+) m/z = 216.0

(M⁺+1). Anal. Calcd for C₁₂H₁₃N₃O C, 66.96; H, 6.09; N, 19.52.

Found C, 67.24; H, 6.28; N, 19.30.

4.1.2.2. 2-(4-Ethylpiperazin-1-yl)-N-(2-methyl-6-nitroquinolin-

4-yl)acetamide (19). 69% as a light yellow solid, mp 189–190 °C;

4.1.3.4. N-(6-Amino-2-methylquinolin-4-yl)-2-(4-methylpipera-

zin-1-yl)acetamide (21). 76% as a white solid, mp 225–227 °C;

m_max(KBr) 1702 (CO), 3213 (NH) cm^{ꢂ1 1}H NMR (CDCl₃, 300 MHz)

;

d = 1.17 (t, 3H, J = 7.2 Hz, CH₂CH₃), 2.61 (q, 2H, J = 7.2 Hz, CH₂CH₃),

2.79–2.85 (m, 11H, CH₃and 4ꢁ CH₂), 3.34 (s, 2H, CH₂), 8.15 (d, 1H,

J = 9.2 Hz, ArH), 8.47–8.51 (m, 2H, ArH), 8.92 (d, 1H, J = 2.3 Hz,

ArH), 10.90 (s, 1H, NH); ¹³C NMR (CDCl₃, 75 MHz) d = 10.8, 24.9,

50.9, 51.9, 52.4, 60.7, 109.8, 115.2, 115.9, 121.6, 130.1, 140.1,

143.2, 149.4, 163.6, 168.0; mass (ES+) m/z = 358.2 (M⁺+1). Anal.

Calcd for C₁₈H₂₃N₅O₃C, 60.49; H, 6.49; N, 19.59. Found C, 60.77;

H, 6.68; N, 19.41.

m_max(KBr) 1718 (CO), 3453 (NH and NH₂) cm^{ꢂ1 1}H NMR (DMSO-

;

d₆, 300 MHz) d = 2.43 (s, 3H, CH₃), 2.74–2.77 (m, 7H, CH₃and 2ꢁ

CH₂), 3.31 (s, 2H, CH₂), 3.34 (s, 4H, 2ꢁ CH₂), 5.64 (br s, 2H, NH₂),

6.80 (s, 1H, ArH), 7.14 (dd, 1H, J₁= 1.5 Hz, J₂= 8.9 Hz, ArH), 7.61

(d, 1H, J = 8.9 Hz, ArH), 7.84 (s, 1H, ArH), 9.88 (s, 1H, NH); ¹³C

NMR (DMSO-d₆, 75 MHz) d = 25.0, 44.8, 52.0, 54.3, 61.6, 98.8,

111.8, 120.9, 121.8, 130.1, 138.5, 142.6, 147.0, 153.3, 169.3; mass

(ES+) m/z = 313.9 (M⁺+1). Anal. Calcd for C₁₇H₂₃N₅O C, 65.15; H,

7.40; N, 22.35. Found C, 64.91; H, 7.62; N, 22.05.

4.1.2.3. N-(2-Methyl-6-nitroquinolin-4-yl)-2-piperidin-1-ylacet-

amide (20). 88% as a brown solid, mp 176–178 °C; m_max(KBr)

4.1.3.5. N-(6-Amino-2-methylquinolin-4-yl)-2-(4-ethylpipera-

zin-1-yl)acetamide (22). 83% as an off white solid, mp 201–

1719 (CO), 3451 (NH) cm^ꢂ^{1 1}H NMR (CDCl₃, 300 MHz) d = 1.63–

;

212

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

202 °C; m_max(KBr) 1694 (CO), 3186 (NH₂), 3399 (NH) cm^ꢂ1

;

¹H

gel or alumina and puriﬁed by column chromatography using hex-

anes/EtOAc (40-10:60-90, v/v) as the eluent to yield the desired

compounds 13–14a–o, 15a–g,i–o, 16a,c,f,h, j,l–m,o, 17a,h,j,m,

24a–m,o, 25g,j,l–m, 26a,g,i,l–m,o.

NMR (CDCl₃, 300 MHz) d = 1.02 (t, 3H, J = 7.1 Hz, CH₂CH₃), 2.39

(q, 2H, J = 7.1 Hz, CH₂CH₃), 2.50 (s, 7H, CH₃and 2ꢁ CH₂), 2.62 (s,

4H, 2ꢁ CH₂), 3.25 (s, 2H, CH₂), 5.55 (s, 2H, NH₂), 6.75 (d, 1H,

J = 1.7 Hz, ArH), 7.14 (dd, 1H, J₁= 1.9 Hz, J₂= 8.9 Hz, ArH), 7.62 (d,

1H, J = 8.9 Hz, ArH), 7.87 (s, 1H, ArH), 9.91 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 50 MHz) d = 12.5, 25.0, 51.8, 52.8, 53.3, 62.0, 98.4,

111.3, 120.6, 121.7, 130.2, 138.3, 142.6, 146.8, 153.3, 169.4; mass

(ES+) m/z = 328.1 (M⁺+1). Anal. Calcd for C₁₈H₂₅N₅O C, 66.03; H,

7.70; N, 21.39. Found C, 66.31; H, 7.53; N, 21.47.

4.1.5.1. N-(6-{[(4-Chloroanilino)carbonyl]amino}-2-methylqui-

nolin-4-yl)benzamide (13a). 68% as a yellow solid, mp 263–

264 °C; tR = 21.73 min; m_max(KBr) 1644, 1665 (CO), 3254 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.62 (s, 3H, CH₃), 7.31 (d,

;

2H, J = 8.7 Hz, ArH), 7.48 (d, 2H, J = 8.8 Hz, ArH), 7.59–7.62 (m,

4H, ArH), 7.86 (s, 2H, ArH), 8.07 (d, 3H, J = 6.3 Hz, ArH), 8.89 (s,

1H, NH), 9.05 (s, 1H, NH), 10.56 (s, 1H, NH); mass (FAB+) m/

z = 431 (M⁺+1). Anal. Calcd for C₂₄H₁₉ClN₄O₂C, 66.90; H, 4.44; N,

13.00. Found C, 66.61; H, 4.60; N, 13.23.

4.1.3.6. N-(6-Amino-2-methylquinolin-4-yl)-2-piperidin-1-yla-

cetamide (23). 82% as an off white solid, mp 208–210 °C; m_max

(KBr) 1688 (CO), 3423 (NH and NH₂) cm^{ꢂ1 1}H NMR (CDCl₃,

;

300 MHz) d = 1.58–1.60 (m, 2H, CH₂), 1.72–1.80 (m, 4H, 2ꢁ CH₂),

2.68 (s, 7H, CH₃and 2ꢁ CH₂), 3.22 (s, 2H, CH₂), 3.96 (s, 2H, NH₂),

6.86 (d, 1H, J = 2.4 Hz, ArH), 7.15 (dd, 1H, J₁= 2.4 Hz, J₂= 8.9 Hz,

ArH), 7.87 (d, 1H, J = 8.9 Hz, ArH), 8.19 (s, 1H, ArH), 10.18 (s, 1H,

NH); ¹³C NMR (CDCl₃, 75 MHz) d = 23.5, 25.2, 26.6, 99.8, 110.8,

119.6, 121.0, 130.8, 138.1, 143.5, 144.1, 156.0, 169.4; mass (ES+)

m/z = 299.1 (M⁺+1). Anal. Calcd for C₁₇H₂₂N₄O C, 68.43; H, 7.43;

N, 18.78. Found C, 68.35; H, 7.68; N, 18.59.

4.1.5.2. N-(6-{[(4-Fluoroanilino)carbonyl]amino}-2-methylqui-

nolin-4-yl)benzamide (13b). 77% as a white solid, mp 256–

257 °C; m_max(KBr) 1651, 1698 (CO), 3369 (NH) cm^{ꢂ1 1}H NMR

;

(DMSO-d₆, 300 MHz) d = 2.61 (s, 3H, CH₃), 7.07–7.14 (m, 2H,

ArH), 7.43–7.57 (m, 6H, ArH), 7.84 (d, 2H, J = 9.9 Hz, ArH), 8.05–

8.09 (m, 3H, ArH), 8.79 (s, 1H, NH), 9.02 (s, 1H, NH), 10.62 (s, 1H,

NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 25.1, 109.5, 115.5, 155.9,

117.7, 120.5, 122.8, 123.3, 128.3, 128.9, 129.4, 132.4, 134.5,

136.2, 137.3, 141.6, 145.2, 153.1, 156.9, 166.5; mass (FAB+) m/

z = 415 (M⁺+1). Anal. Calcd for C₂₄H₁₉FN₄O₂C, 69.55; H, 4.62; N,

13.52. Found C, 69.38; H, 4.82; N, 13.49.

4.1.4. General procedure for the preparation of N-(6-amino-2-

methylquinolin-4-yl)-chlorobenzamides (9–10)

A solution of chloro-N-(2-methyl-6-nitroquinolin-4-yl)benzam-

ide 3–4 (5.86 mmol, 2.0 g) and anhydrous SnCl₂ꢀ2H₂O

(29.32 mmol, 5.56 g) in MeOH (20 mL) was heated at reﬂux tem-

perature for half an hour under nitrogen atmosphere. Thereafter

excessive MeOH was evaporated and the residue was dissolved

in EtOAc (100 mL) and basiﬁed with aqueous NaHCO₃solution.

The resulting mixture was ﬁltered through a celite bed followed

by separation of organic layer via partitioning. Organic layer was

collected, dried over anhydrous Na₂SO₄and concentrated under re-

duced pressure to obtain the desired N-(6-amino-2-methylquino-

lin-4-yl)-chlorobenzamides (9–10) which were further puriﬁed

by silica gel column chromatography with MeOH/CHCl₃(2:98, v/

v) as eluent and recrystallized from MeOH.

4.1.5.3. N-(6-{[(4-Bromoanilino)carbonyl]amino}-2-methylqui-

nolin-4-yl)benzamide (13c). 71% as a white solid, mp 245–

246 °C; tR = 21.14 min; m_max(KBr), 1644, 1665 (CO), 3251 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.62 (s, 3H, CH₃), 7.43 (s,

;

3H, ArH), 7.59–7.66 (m, 5H, ArH), 7.85–7.86 (m, 2H, ArH), 8.08

(d, 3H, J = 6.9 Hz, ArH), 8.90 (s, 1H, NH), 9.05 (s, 1H, NH), 10.57

(s, 1H, NH); mass (FAB+) m/z = 475 (M⁺+1). Anal. Calcd for

C₂₄H₁₉BrN₄O₂C, 60.64; H, 4.03; N, 11.79. Found C, 60.77; H,

4.21; N, 11.35.

4.1.5.4. N-(6-{[(3-Chloroanilino)carbonyl]amino}-2-methylqui-

nolin-4-yl)benzamide (13d). 81% as a white solid, mp 259–

260 °C; tR = 17.12 min; m_max(KBr) 1645, 1697 (CO), 3298 (NH)

4.1.4.1. N-(6-Amino-2-methylquinolin-4-yl)-2-chlorobenzam-

ide (9). 67% as a yellow solid, mp 191–193 °C; m_max(KBr) 1654

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.66 (s, 3H, CH₃), 7.02 (s,

;

(CO), 3358 (NH and NH₂) cm^ꢂ1

;

¹H NMR (DMSO-d₆, 300 MHz)

1H, ArH), 7.29 (d, 2H, J = 4.2 Hz, ArH), 7.57–7.72 (m, 5H, ArH),

7.91 (s, 2H, ArH), 8.09 (d, 2H, J = 7.1 Hz, ArH), 8.17 (s, 1H, ArH),

9.11 (s, 1H, NH), 9.24 (s, 1H, NH), 10.67 (s, 1H, NH); mass (ES+)

m/z = 431.0 (M⁺+1). Anal. Calcd for C₂₄H₁₉ClN₄O₂C, 66.90; H,

4.44; N, 13.00. Found C, 66.81; H, 4.63; N, 12.74.

d = 2.69 (s, 3H, CH₃), 3.75 (br s, 2H, NH₂), 6.93 (s, 1H, ArH), 7.11

(d, 1H, J = 7.6 Hz, ArH), 7.50–7.67 (m, 3H, ArH), 7.85 (d, 1H,

J = 7.0 Hz, ArH), 7.98 (d, 1H, J = 6.5 Hz, ArH), 8.20 (d, 1H,

J = 6.3 Hz, ArH); mass (FAB+) m/z = 312 (M⁺+1). Anal. Calcd for

C₁₇H₁₄ClN₃O C, 65.49; H, 4.53; N, 13.48. Found C, 65.26; H, 4.46;

N, 13.80.

4.1.5.5. N-(6-{[(3-Fluoroanilino)carbonyl]amino}-2-methylqui-

nolin-4-yl)benzamide (13e). 80% as a white solid, mp 258–

4.1.4.2. N-(6-Amino-2-methylquinolin-4-yl)-3-chlorobenzam-

ide (10). 62% as a yellow solid, mp 179–181 °C; m_max(KBr) 1697

259 °C; m_max(KBr) 1651, 1693 (CO), 3350 (NH) cm^{ꢂ1 1}H NMR

;

(DMSO-d₆, 300 MHz) d = 2.72 (s, 3H, CH₃), 6.80 (t, 1H, J = 7.4 Hz,

ArH), 7.16 (d, 1H, J = 8.1 Hz, ArH), 7.27–7.35 (m, 1H, ArH), 7.49–

7.71 (m, 4H, ArH), 7.90 (s, 1H, ArH), 7.99 (s, 2H, ArH), 8.12 (d,

2H, J = 7.2 Hz, ArH), 8.31 (s, 1H, ArH), 9.50 (s, 1H, NH), 9.61 (s,

1H, NH), 10.85 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 22.3,

103.9, 104.2, 107.4, 107.6, 108.5, 113.1, 115.2, 120.9, 123.6,

125.3, 127.3, 127.8, 129.6, 131.6, 133.1, 136.8, 140.7, 143.1,

151.7, 155.0, 160.0, 163.2, 165.7; mass (ES+) m/z = 415.1 (M⁺+1).

Anal. Calcd for C₂₄H₁₉FN₄O₂C, 69.55; H, 4.62; N, 13.52. Found C,

69.68; H, 4.94; N, 13.40.

(CO), 3313 (NH and NH₂) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz)

;

d = 2.81 (s, 3H, CH₃), 7.30–7.33 (m, 1H, ArH), 7.46 (dd, 1H,

J₁= 2.1 Hz, J₂= 9.1 Hz, ArH), 7.61–7.71 (m, 2H, ArH), 7.97–8.00

(m, 1H, ArH), 8.08–8.15 (m, 2H, ArH), 8.20 (s, 1H, ArH), 10.89 (s,

1H, NH); mass (FAB+) m/z = 312 (M⁺+1). Anal. Calcd for

C₁₇H₁₄ClN₃O C, 65.49; H, 4.53; N, 13.48. Found C, 65.78; H, 4.73;

N, 13.17.

4.1.5. General procedure for the preparation of compounds 13–

14a–o, 15a–g,i–o, 16a,c,f,h, j,l–m,o, 17a,h,j,m, 24a–m,o, 25g,j,l–

m, 26a,g,i,l–m,o

A mixture of appropriate amine from 8–12, 21–23 (1.16 mmol)

and aryl isocyanate or activated carbamate (1.28 mmol) in anhy-

drous MeCN or THF (10 mL) was stirred at room temperature for

2 min-6 h. Thereafter, the reaction mixture was adsorbed on silica

4.1.5.6. N-(6-{[(3-Cyanoanilino)carbonyl]amino}-2-methylqui-

nolin-4-yl)benzamide (13f). 53% as a yellow solid, mp 272–

273 °C; tR = 17.70 min; m_max(KBr) 1656, 1703 (CO), 2230 (CN),

3280 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.71 (s, 3H,

;

CH₃), 7.47–7.60 (m, 2H, ArH), 7.63–7.79 (m, 5H, ArH), 7.97–7.99

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

213

(m, 3H, ArH), 8.13 (d, 2H, J = 7.3 Hz, ArH), 8.23 (s, 1H, ArH), 9.31 (s,

1H, NH), 9.39 (s, 1H, NH), 10.74 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

75 MHz) d = 23.2, 108.8, 110.8, 115.9, 118.0, 120.0, 121.2, 122.1,

122.9, 124.6, 127.2, 127.8, 129.4, 131.4, 133.2, 136.1, 139.7,

141.7, 151.8, 155.5, 165.5; mass (FAB+) m/z = 422 (M⁺+1). Anal.

Calcd for C₂₅H₁₉N₅O₂C, 71.25; H, 4.54; N, 16.62. Found C, 71.03;

H, 4.83; N, 16.39.

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.79 (s, 3H, CH₃), 7.38

;

(dd, 1H, J₁= 3.0 Hz, J₂= 9.0 Hz, ArH), 7.54 (d, 1H, J = 9.0 Hz, ArH),

7.60–7.64 (m, 2H, ArH), 7.70 (d, 1H, J = 9.0 Hz, ArH), 7.87 (s, 1H,

ArH), 8.04–8.11 (m, 5H, ArH), 8.38 (s, 1H, ArH), 9.44 (s, 1H, NH),

9.53 (s, 1H, NH), 10.18 (s, 1H, NH); mass (FAB+) m/z = 464

(M⁺+1). Anal. Calcd for C₂₄H₁₈Cl₂N₄O₂C, 61.95; H, 3.90; N, 12.04.

Found C, 61.63; H, 4.01; N, 11.86.

4.1.5.7. N-[2-Methyl-6-({[3-(triﬂuoromethyl)anilino]carbonyl}-

amino)quinolin-4-yl]benzamide (13g). 68% as a white solid,

4.1.5.13. N-(6-{[(3,5-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)benzamide (13m). 69% as a yellow solid, mp

274–275 °C; tR = 19.47 min; m_max(KBr) 1711 (CO), 3424 (NH)

mp 252–254 °C; m_max(KBr) 1656, 1697 (CO), 3346 (NH) cm^{ꢂ1 1}H

;

NMR (DMSO-d₆, 300 MHz) d = 2.74 (s, 3H, CH₃), 7.32 (d, 1H,

J = 5.9 Hz, ArH), 7.52-7.69 (m, 5H, ArH), 8.01–8.11 (m, 6H, ArH),

8.36 (s, 1H, ArH), 9.56 (s, 2H, 2ꢁ NH), 10.90 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 75 MHz) d = 23.3, 109.9, 114.5, 116.2, 118.7, 122.1,

122.2, 122.9, 125.1, 126.1, 128.7, 129.0, 129.8, 130.4, 132.9,

134.4, 138.1, 140.9, 144.7, 153.1, 156.2, 167.1; mass (ES+) m/

z = 465.0 (M⁺+1). Anal. Calcd for C₂₅H₁₉F₃N₄O₂C, 64.65; H, 4.12;

N, 12.06. Found C, 64.83; H, 3.98; N, 11.75.

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.76 (s, 3H, CH₃), 7.17 (s,

;

1H, ArH), 7.54–7.69 (m, 5H, ArH), 8.03–8.10 (m, 5H, ArH), 8.37 (s,

1H, ArH), 9.76 (s, 2H, 2ꢁ NH), 10.98 (s, 1H, NH); mass (ES+) m/

z = 465.1 (M⁺+1), 467.1 (M⁺+3). Anal. Calcd for C₂₄H₁₈Cl₂N₄O₂C,

61.95; H, 3.90; N, 12.04. Found C, 62.23; H, 3.68; N, 12.31.

4.1.5.14. N-(6-{[(3-Chloro-4-ﬂuoroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (13n). 79% as a white solid,

mp 247–248 °C; m_max(KBr) 1657, 1699 (CO), 3328 (NH) cm^{ꢂ1 1}H

;

4.1.5.8. N-(6-{[(4-Acetylanilino)carbonyl]amino}-2-methylqui-

nolin-4-yl)benzamide (13h). 59% as a white solid, mp 293–

294 °C; tR = 17.06 min; m_max(KBr) 1670, 1708 (CO), 3252 (NH)

NMR (DMSO-d₆, 300 MHz) d = 2.62 (s, 3H, CH₃), 7.11 (t, 2H,

J = 8.8 Hz, ArH), 7.43–7.48 (m, 2H, ArH), 7.59–7.66 (m, 4H, ArH),

7.86 (d, 2 H, J = 2.4 Hz, ArH), 8.07 (s, 2H, ArH), 8.10 (s, 1H, ArH),

8.79 (s, 1H, NH), 9.02 (s, 1H, NH), 10.62 (s, 1H, NH); mass (ES+)

m/z = 449.1 (M⁺+1). Anal. Calcd for C₂₄H₁₉ClFN₄O₂C, 64.22; H,

4.04; N, 12.48. Found C, 64.33; H, 4.28; N, 12.51.

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.50 (s, 3H, CH₃), 2.86 (s,

;

3H, CH₃), 7.59-7.72 (m, 5H, ArH), 7.90 (d, 2H, J = 8.3 Hz, ArH),

8.08–8.20 (m, 4H, ArH), 8.33 (s, 1H, ArH), 8.62 (s, 1H, ArH), 10.03

(s, 1H, NH), 10.15 (s, 1H, NH), 11.26 (s, 1H, NH); mass (FAB+) m/

z = 439 (M⁺+1). Anal. Calcd for C₂₆H₂₂N₄O₃C, 71.22; H, 5.06; N,

12.78. Found C, 71.39; H, 4.95; N, 12.56.

4.1.5.15. N-[6-({[4-Chloro-3-(triﬂuoromethyl)anilino]carbonyl}-

amino)-2-methylquinolin-4-yl]acetamidebenzamide (13o). 64%

as a white solid, mp 205–208 °C; m_max(KBr) 1687 (CO), 3533

4.1.5.9. N-(6-{[(3-Acetylanilino)carbonyl]amino}-2-methylqui-

nolin-4-yl)benzamide (13i). 90% as a light yellow solid, mp

241–242 °C; tR = 15.56 min; m_max(KBr) 1629, 1683 (CO), 3291

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.65 (s, 3H, CH₃),

;

7.57–7.69 (m, 6H, ArH), 7.90 (s, 2H, ArH), 8.08–8.11 (m, 3H, ArH),

8.17 (s, 1H, ArH), 9.26 (s, 1H, NH), 9.32 (s, 1H, NH), 10.63 (s, 1H,

NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 23.7, 108.9, 116.0, 116.3,

121.4, 121.6, 122.3, 122.5, 127.2, 127.7, 131.2, 131.3, 133.3,

135.7, 138.4, 140.9, 143.5, 151.7, 155.8, 165.4; mass (ES+) m/

z = 499.2 (M⁺+1), 501.2 (M⁺+3). Anal. Calcd for C₂₅H₁₈ClF₃N₄O₂C,

60.19; H, 3.64; N, 11.23. Found C, 60.02; H, 3.91; N, 11.05.

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.59 (s, 3H, CH₃),

;

2.66 (s, 3H, CH₃), 7.42–7.50 (m, 1H, ArH), 7.60–7.74 (m, 6H, ArH),

7.91 (s, 2H, ArH), 8.13 (d, 4H, J = 9.8 Hz, ArH), 9.01 (s, 1H, NH),

9.09 (s, 1H, NH), 10.59 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz)

d = 25.1, 27.1, 109.7, 117.8, 122.5, 122.7, 123.3, 128.3, 128.9,

129.6, 132.4, 134.6, 137.1, 137.8, 140.4, 141.6, 145.2, 153.0,

157.0, 166.6, 198.1; mass (ES+) m/z = 439.1 (M⁺+1). Anal. Calcd

for C₂₆H₂₂N₄O₃C, 71.22; H, 5.06; N, 12.78. Found C, 71.48; H,

5.00; N, 12.41.

4.1.5.16. 2-Chloro-N-(6-{[(4-chloroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (14a). 91% as a white solid,

mp 224–225 °C; m_max(KBr) 1653 (CO), 3282 (NH) cm^{ꢂ1 1}H NMR

;

(DMSO-d₆, 200 MHz) d = 2.63 (s, 3H, CH₃), 7.32 (s, 1H, ArH), 7.36

(s, 1H, ArH), 7.49–7.60 (m, 5H, ArH), 7.70–7.76 (m, 2H, ArH), 7.86

(s, 2H, ArH), 8.20 (s, 1H, ArH), 9.07 (s, 1H, NH), 9.09 (s, 1H, NH),

10.78 (s, 1H, NH); mass (ES+) m/z = 465.1 (M⁺+1), 467.1 (M⁺+3).

Anal. Calcd for C₂₄H₁₈Cl₂N₄O₂C, 61.95; H, 3.90; N, 12.04. Found

C, 62.24; H, 3.99; N, 12.22.

4.1.5.10. N-(6-{[(3-Chloro-4-methylanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (13j). 75% as a light yellow so-

lid, mp 254–255 °C; tR = 22.58 min; m_max(KBr) 1656, 1700 (CO),

3353 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.27 (s, 3H,

;

CH₃), 2.88 (s, 3H, CH₃), 7.26 (s, 2H, ArH), 7.62–7.76 (m, 4H, ArH),

8.10–8.17 (m, 4H, ArH), 8.33 (s, 1H, ArH), 8.58 (s, 1H, ArH), 9.61

(s, 1H, NH), 9.92 (s, 1H, NH), 11.21 (s, 1H, NH); mass (FAB+) m/

z = 445 (M⁺+1). Anal. Calcd for C₂₅H₂₁ClN₄O₂C, 67.49; H, 4.76; N,

12.59. Found C, 67.21; H, 4.75; N, 12.37.

4.1.5.17. 2-Chloro-N-(6-{[(4-ﬂuoroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (14b). 95% as a white solid,

mp 264–266 °C; tR = 16.80 min; m_max(KBr) 1645 (CO), 3273 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.66 (s, 3H, CH₃), 7.16 (t,

;

4.1.5.11. N-(6-{[(3-Chloro-2-methylanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (13k). 78% as a yellow solid,

mp 242–244 °C; tR = 20.89 min; m_max(KBr) 1640 (CO), 3285 (NH)

2H, J = 8.8 Hz, ArH), 7.48–7.66 (m, 5H, ArH), 7.73–7.78 (m, 2H,

ArH), 7.89 (s, 2H, ArH), 8.21 (s, 1H, ArH), 8.86 (s, 1H, NH), 8.95 (s,

1H, NH), 10.80 (s, 1H, NH); mass (FAB+) m/z = 449 (M⁺+1). Anal.

Calcd for C₂₄H₁₈ClFN₄O₂C, 64.22; H, 4.04; N, 12.48. Found C,

63.97; H, 4.31; N, 12.61.

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.29 (s, 3H, CH₃), 2.63 (s,

;

3H, CH₃), 7.15–7.18 (m, 2H, ArH), 7.57–7.66 (m, 4H, ArH), 7.72–

7.75 (m, 1H, ArH), 7.89 (s, 2H, ArH), 8.07–8.10 (m, 3H, ArH), 8.24

(s, 1H, NH), 9.37 (s, 1H, NH), 10.60 (s, 1H, NH); mass (FAB+) m/

z = 445 (M⁺+1). Anal. Calcd for C₂₅H₂₁ClN₄O₂C, 67.49; H, 4.76; N,

12.59. Found C, 67.16; H, 4.81; N, 12.36.

4.1.5.18. N-(6-{[(4-Bromoanilino)carbonyl]amino}-2-methyl-

quinolin-4-yl)-2-chlorobenzamide (14c). 92% as a white solid,

mp 136–138 °C; tR = 21.38 min; m_max(KBr) 1645, 1689 (CO), 3356

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.66 (s, 3H, CH₃),

;

4.1.5.12. N-(6-{[(3,4-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)benzamide (13l). 74% as an off white solid, mp

239–240 °C; tR = 19.15 min; m_max(KBr) 1703 (CO), 3371 (NH)

7.47–7.50 (m, 3H, ArH), 7.53–7.66 (m, 3H, ArH), 7.73–7.80 (m,

2H, ArH), 7.90 (s, 2H, ArH), 8.13 (d, 1H, J = 6.9 Hz, ArH), 8.23 (s,

1H, ArH), 8.99 (s, 1H, NH), 9.01 (s, 1H, NH), 10.82 (s, 1H, NH); ¹³C

214

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

NMR (DMSO-d₆, 50 MHz) d = 25.2, 109.7, 113.7, 116.0, 117.7, 120.5,

121.7, 122.8, 123.6, 127.6, 128.9, 129.6, 130.1, 130.5, 131.7, 136.9,

137.0, 139.4, 140.8, 141.6, 145.3, 152.8, 157.0, 166.4; mass (FAB+)

m/z = 509 (M⁺+1). Anal. Calcd for C₂₄H₁₈BrClN₄O₂C, 56.55; H, 3.56;

N, 10.99. Found C, 56.79; H, 3.71; N, 10.78.

4.1.5.24. N-(6-{[(3-Acetylanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-chlorobenzamide (14i). 87% as a yellow solid,

mp 245–247 °C; m_max(KBr) 1679, 1728 (CO), 3392 (NH) cm^{ꢂ1 1}H

;

NMR (DMSO-d₆, 200 MHz) d = 2.59 (s, 3H, COCH₃), 2.66 (s, 3H,

CH₃), 7.44–7.83 (m, 8H, ArH), 7.88–7.95 (m, 2H, ArH), 8.14 (s, 1H,

ArH), 8.29 (s, 1H, ArH), 9.05 (s, 1H, NH), 9.08 (s, 1H, NH), 10.86

(s, 1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 25.0, 27.1, 109.8,

116.1, 117.8, 121.8, 122.5, 123.3, 123.8, 127.6, 128.3, 129.6,

130.1, 130.5, 131.8, 136.8, 137.1, 137.7, 140.3, 141.1, 144.9,

153.0, 157.1, 166.5, 198.3; mass (FAB+) m/z = 473 (M⁺+1). Anal.

Calcd for C₂₆H₂₁ClN₄O₃C, 66.03; H, 4.48; N, 11.85. Found C,

65.79; H, 4.77; N, 12.09.

4.1.5.19. 2-Chloro-N-(6-{[(3-chloroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (14d). 94% as a white solid,

mp 242–243 °C; m_max(KBr) 1652, 1697 (CO), 3383 (NH) cm^{ꢂ1 1}H

;

NMR (DMSO-d₆, 200 MHz) d = 2.66 (s, 3H, CH₃), 7.06 (d, 1H,

J = 8.7 Hz, ArH), 7.32 (s, 2H, ArH), 7.50–7.66 (m, 3H, ArH), 7.73–

7.83 (m, 3H, ArH), 7.89 (s, 2H, ArH), 8.24 (s, 1H, ArH), 9.07 (s, 2H,

2ꢁ NH), 10.84 (s, 1H, NH); mass (FAB+) m/z = 465 (M⁺+1). Anal.

Calcd for C₂₄H₁₈Cl₂N₄O₂C, 61.95; H, 3.90; N, 12.04. Found C,

62.04; H, 3.68; N, 12.29.

4.1.5.25. 2-Chloro-N-(6-{[(3-chloro-4-methylanilino)carbonyl]-

amino}-2-methylquinolin-4-yl)benzamide (14j). 98% as

white solid, mp 137–139 °C; tR = 22.15 min; m_max(KBr) 1658,

1685 (CO), 3353 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz)

a

4.1.5.20. 2-Chloro-N-(6-{[(3-ﬂuoroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (14e). 94% as a white solid,

;

d = 2.25 (s, 3H, CH₃), 2.62 (s, 3H, CH₃), 7.23 (s, 2H, ArH), 7.50–

7.62 (m, 3H, ArH), 7.72–7.74 (m, 3H, ArH), 7.85 (s, 2H, ArH), 8.20

(s, 1H, ArH), 9.12 (s, 1H, NH), 9.20 (s, 1H, NH), 10.78 (s, 1H, NH);

¹³C NMR (DMSO-d₆, 50 MHz) d = 19.2, 25.1, 109.7, 116.0, 117.5,

118.6, 121.7, 123.4, 127.6, 128.3, 128.8, 129.5, 130.5, 131.6,

132.4, 133.5, 134.5, 137.1, 139.1, 140.8, 141.5, 145.3, 152.9,

157.0, 166.4; mass (FAB+) m/z = 479 (M⁺+1). Anal. Calcd for

C₂₅H₂₀Cl₂N₄O₂C, 62.64; H, 4.21; N, 11.69. Found C, 62.92; H,

3.96; N, 11.47.

mp 243–245 °C; m_max(KBr) 1641, 1697 (CO), 3288 (NH) cm^{ꢂ1 1}H

;

NMR (DMSO-d₆, 300 MHz) d = 2.64 (s, 3H, CH₃), 6.80 (dt, 1H,

J₁= 2.3 Hz, J₂= 8.4 Hz, ArH), 7.15 (dd, 1H, J₁= 1.0 Hz, J₂= 8.2 Hz,

ArH), 7.28–7.36 (m, 1H, ArH), 7.49–7.64 (m, 4H, ArH), 7.71–7.77

(m, 2H, ArH), 7.83–7.91 (m, 2H, ArH), 8.21 (d, 1H, J = 1.1 Hz,

ArH), 9.04 (s, 1H, NH), 9.07 (s, 1H, NH), 10.78 (s, 1H, NH); mass

(FAB+) m/z = 449 (M⁺+1). Anal. Calcd for C₂₄H₁₈ClFN₄O₂C, 64.22;

H, 4.04; N, 12.48. Found C, 64.51; H, 4.01; N, 12.73.

4.1.5.21. 2-Chloro-N-(6-{[(3-cyanoanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (14f). 92% as a white solid, mp

4.1.5.26. 2-Chloro-N-(6-{[(3-chloro-2-methylanilino)carbonyl]-

amino}-2-methylquinolin-4-yl)benzamide (14k). 90% as

white solid, mp 272–274 °C; m_max(KBr) 1649 (CO), 3288 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.29 (s, 3H, CH₃), 2.62 (s,

a

257–259 °C; tR = 16.89 min;

m_max(KBr) 1649, 1699 (CO), 2230 (CN),

3354 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.67 (s, 3H,

;

CH₃), 7.44–7.67 (m, 5H, ArH), 7.73–7.80 (m, 2H, ArH), 7.91 (s, 2H,

ArH), 8.03 (s, 1H, ArH), 8.12 (d, 1H, J = 3.1 Hz, ArH), 8.24 (s, 1H,

ArH), 9.14 (s, 1H, NH), 9.18 (s, 1H, NH), 10.83 (s, 1H, NH); ¹³C

NMR (DMSO-d₆, 50 MHz) d = 25.2, 110.1, 112.0, 116.0, 119.2,

121.3, 121.7, 123.3, 123.7, 125.8, 127.6, 128.3, 128.9, 129.6,

130.1, 130.5, 131.7, 132.4, 136.8, 140.9, 145.4, 152.9, 157.2,

166.4; mass (FAB+) m/z = 456 (M⁺+1). Anal. Calcd for C₂₅H₁₈ClN₅O₂

C, 65.86; H, 3.98; N, 15.36. Found C, 65.59; H, 4.13; N, 15.14.

3H, CH₃), 7.16–7.19 (m, 2H, ArH), 7.48–7.61 (m, 3H, ArH), 7.66–

7.77 (m, 3H, ArH), 7.86 (s, 2H, ArH), 8.17 (s, 1H, ArH), 8.27 (s, 1H,

NH), 9.29 (s, 1H, NH), 10.60 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

50 MHz) d = 15.0, 25.1, 109.4, 115.9, 121.2, 121.7, 123.4, 124.1,

126.9, 127.2, 127.5, 139.3, 130.0, 130.4, 131.7, 133.9, 136.8,

137.2, 139.2, 140.7, 145.2, 153.0, 156.9, 166.3; mass (FAB+) m/

z = 473 (M⁺+1). Anal. Calcd for C₂₅H₂₀Cl₂N₄O₂C, 62.64; H, 4.21;

N, 11.69. Found C, 62.47; H, 4.40; N, 11.67.

4.1.5.22. 2-Chloro-N-[2-methyl-6-({[3-(triﬂuoromethyl)anili-

no]carbonyl}amino)quinolin-4-yl]benzamide (14g). 94% as a

light yellow solid, mp 234–236 °C; m_max(KBr) 1692 (CO), 3312

4.1.5.27. 2-Chloro-N-(6-{[(3,4-dichloroanilino)carbonyl]amino}-

2-methylquinolin-4-yl)benzamide (14l). 84% as a white solid,

mp 223–224 °C; m_max(KBr) 1702 (CO), 3303 (NH) cm^{ꢂ1 1}H NMR

;

(NH) cm^ꢂ1

;

¹H NMR (DMSO-d₆, 300 MHz) d = 2.64 (s, 3H, CH₃),

(DMSO-d₆, 300 MHz) d = 2.64 (s, 3H, CH₃), 7.36 (dd, 1H,

J₁= 2.1 Hz, J₂= 8.7 Hz, ArH), 7.51–7.63 (m, 4H, ArH), 7.71–7.77

(m, 2H, ArH), 7.83–7.92 (m, 3H, ArH), 8.22 (s, 1H, ArH), 9.10 (s,

1H, NH), 9.15 (s, 1H, NH), 10.79 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

75 MHz) d = 25.3, 110.2, 116.1, 118.8, 119.8, 121.8, 123.7, 123.8,

127.7, 129.7, 130.2, 130.6, 131.1, 131.5, 131.8, 136.9, 137.0,

140.4, 141.0, 145.5, 152.9, 157.3, 166.5; mass (ES+) m/z = 499.1

(M⁺+1), 501.1 (M⁺+3). Anal. Calcd for C₂₄H₁₇Cl₃N₄O₂C, 57.68; H,

3.43; N, 11.21. Found C, 58.01; H, 3.54; N, 11.47.

7.33 (d, 1H, J = 7.4 Hz, ArH), 7.51–7.63 (m, 5H, ArH), 7.73–7.77

(m, 2H, ArH), 7.85–7.91 (m, 2H, ArH), 8.08 (s, 1H, ArH), 8.25 (s,

1H, ArH), 9.06 (s, 1H, NH), 9.18 (s, 1H, NH), 10.79 (s, 1H, NH); ¹³C

NMR (DMSO-d₆, 50 MHz) d = 25.2, 110.0, 114.5, 116.1, 118.5,

121.7, 122.2, 123.7, 127.5, 129.0, 129.6, 130.0, 130.3, 130.5,

131.7, 136.9, 140.9, 145.4, 153.0, 157.1, 166.4; mass (FAB+) m/

z = 499 (M⁺+1). Anal. Calcd for C₂₅H₁₈ClF₃N₄O₂C, 60.19; H, 3.64;

N, 11.23. Found C, 60.53; H, 3.84; N, 11.02.

4.1.5.23. N-(6-{[(4-Acetylanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-chlorobenzamide (14h). 93% as a white solid, mp

4.1.5.28. 2-Chloro-N-(6-{[(3,5-dichloroanilino)carbonyl]amino}-

2-methylquinolin-4-yl)benzamide (14m). 87% as a off-white

221–223 °C; tR = 22.15 min;

m

_max(KBr) 1641, 1699 (CO), 3353 (NH)

solid, mp >250 °C; m_max(KBr) 1696 (CO), 3324 (NH) cm^{ꢂ1 1}H

;

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.52 (s, 3H, CH₃), 2.64 (s,

;

NMR (DMSO-d₆, 300 MHz) d = 2.63 (s, 3H, CH₃), 7.16 (t, 1H,

J = 1.8 Hz, ArH), 7.49–7.62 (m, 5H, ArH), 7.71 (dd, 1H, J₁= 1.4 Hz,

J₂= 7.1 Hz, ArH), 7.76 (s, 1H, ArH), 7.81–7.89 (m, 2H, ArH), 8.20

(d, 1H, J = 1.7 Hz, ArH), 9.12 (s, 1H, NH), 9.16 (s, 1H, NH), 10.77

(s, 1H, NH); mass (ES+) m/z = 499.2 (M⁺+1), 501.1 (M⁺+3). Anal.

Calcd for C₂₄H₁₇Cl₃N₄O₂C, 57.68; H, 3.43; N, 11.21. Found C,

57.93; H, 3.61; N, 11.08.

3H, CH₃), 7.52–7.63 (m, 5H, ArH), 7.71–7.74 (m, 1H, ArH), 7.78 (s,

1H, ArH), 7.87–7.94 (m, 4H, ArH), 8.24 (s, 1H, ArH), 9.09 (s, 1H,

NH), 9.25 (s, 1H, NH), 10.83 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

75 MHz) d = 25.3, 26.8, 110.0, 116.1, 117.7, 121.8, 123.7, 127.7,

128.4, 129.0, 129.7, 130.2, 130.6, 131.0, 131.8, 136.9, 137.0,

141.0, 144.7, 145.4, 152.7, 157.3, 166.5, 196.8; mass (ES+) m/

z = 473.1 (M⁺+1), 475.1 (M⁺+3). Anal. Calcd for C₂₆H₂₁ClN₄O₃C,

66.03; H, 4.48; N, 11.85. Found C, 66.24; H, 4.55; N, 12.06.

4.1.5.29. 2-Chloro-N-(6-{[(3-chloro-4-ﬂuoroanilino)carbonyl]-

amino}-2-methylquinolin-4-yl)benzamide (14n). 90% as

a

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

215

white solid, mp 256–258 °C; tR = 18.24 min;

m

_max(KBr) 1673 (CO),

NH), 9.10 (s, 1H, NH), 10.58 (s, 1H, NH); mass (ES+) m/z = 465.2

(M⁺+1), 487.1 (M⁺+Na). Anal. Calcd for C₂₄H₁₈Cl₂N₄O₂C, 61.95; H,

3.90; N, 12.04. Found C, 62.28; H, 4.18; N, 11.79.

3414 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.68 (s, 3H,

;

CH₃), 7.37 (d, 2H, J = 6.6 Hz, ArH), 7.44–7.68 (m, 3H, ArH), 7.75–

7.91 (m, 5H, ArH), 8.25 (s, 1H, ArH), 9.05 (s, 1H, NH), 9.07 (s, 1H,

NH), 10.82 (s, 1H, NH); mass (FAB+) m/z = 483 (M⁺+1). Anal. Calcd

for C₂₄H₁₇Cl₂FN₄O₂C, 59.64; H, 3.55; N, 11.59. Found C, 59.92; H,

3.56; N, 11.74.

4.1.5.35. 3-Chloro-N-(6-{[(3-ﬂuoroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (15e). 93% as a white solid,

mp 232–234 °C; m_max(KBr) 1651, 1695 (CO), 3356 (NH) cm^{ꢂ1 1}H

;

NMR (DMSO-d₆, 300 MHz) d = 2.64 (s, 3H, CH₃), 6.77 (dt, 1H,

J₁= 2.2 Hz, J₂= 8.3 Hz, ArH), 7.13–7.16 (m, 1H, ArH), 7.26–7.32

(m, 1H, ArH), 7.48 (td, 1H, J₁= 2.1 Hz, J₂= 11.9 Hz, ArH), 7.57–

7.67 (m, 3H, ArH), 7.82–7.91 (m, 2H, ArH), 8.09–8.12 (m, 2H,

ArH), 8.16 (d, 1H, J = 1.8 Hz, ArH), 9.48 (s, 1H, NH), 9.52 (s, 1H,

NH), 10.58 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 25.3,

105.0, 105.5, 108.5, 108.9, 109.6, 114.4, 118.0, 123.1, 123.5,

128.6, 129.2, 132.7, 134.8, 137.4, 141.8, 145.4, 153.3, 157.1,

165.4, 166.8; mass (FAB+) m/z = 473 (M⁺+1). Anal. Calcd for

C₂₄H₁₈ClFN₄O₂C, 64.22; H, 4.04; N, 12.48. Found C, 64.04; H,

4.30; N, 12.34.

4.1.5.30. 2-Chloro-N-(6-{[(4-chloro-3-triﬂuoromethylanilino)-

carbonyl]amino}-2-methylquinolin-4-yl)benzamide (14o). 84%

as a white solid, mp >250 °C; m_max(KBr) 1671 (CO), 3414 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.63 (s, 3H, CH₃), 7.49–

;

7.63 (m, 5H, ArH), 7.70–7.75 (m, 2H, ArH), 7.83–7.89 (m, 2H,

ArH), 8.15 (s, 1H, ArH), 8.24 (d, 1H, J = 1.6 Hz, ArH), 9.11 (s, 1H,

NH), 9.28 (s, 1H, NH), 10.79 (s, 1H, NH); mass (ES+) m/z = 533.1

(M⁺+1), 535.1 (M⁺+3). Anal. Calcd for C₂₅H₁₇Cl₂F₃N₄O₂C, 56.30;

H, 3.21; N, 10.51. Found C, 56.63; H, 3.17; N, 10.70.

4.1.5.31. 3-Chloro-N-(6-{[(4-chloroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (15a). 86% as an off white so-

lid, mp 238–239 °C; m_max(KBr) 1654, 1693 (CO), 3350 (NH)

4.1.5.36. 3-Chloro-N-(6-{[(3-cyanoanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (15f). 86% as a yellow solid,

cm^ꢂ1

;

¹H NMR (DMSO-d₆, 300 MHz) d = 2.64 (s, 3H, CH₃), 7.33 (d,

mp 221–223 °C;

m_max(KBr) 1664, 1701 (CO), 2236 (CN), 3261

2H, J = 8.8 Hz, ArH), 7.48–7.54 (m, 2H, ArH), 7.61–7.66 (m, 2H,

ArH), 7.72–7.75 (m, 1H, ArH), 7.85–7.93 (m, 2H, ArH), 8.06 (d,

1H, J = 7.7 Hz, ArH), 8.11–8.18 (m, 2H, ArH), 8.92 (s, 1H, NH),

9.07 (s, 1 H, NH), 10.71 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz)

d = 25.2, 109.7, 118.0, 120.3, 122.9, 123.5, 126.1, 127.2, 128.3,

128.5, 129.2, 129.6, 131.1, 132.4, 133.9, 136.7, 137.3, 139.1,

141.4, 145.4, 153.1, 157.1, 165.3, 166.7; mass (ES+) m/z = 465.1

(M⁺+1), 467.1 (M⁺+3). Anal. Calcd for C₂₄H₁₈Cl₂N₄O₂C, 61.95; H,

3.90; N, 12.04. Found C, 61.80; H, 4.08; N, 12.22.

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.68 (s, 3H, CH₃),

;

7.41–7.52 (m, 2H, ArH), 7.61–7.76 (m, 4H, ArH), 7.86–7.96 (m,

2H, ArH), 8.02 (s, 2H, ArH), 8.16 (s, 1H, ArH), 8.28 (s, 1H, ArH),

9.38 (s, 1H, NH), 9.41 (s, 1H, NH), 10.55 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 75 MHz) d = 24.6, 109.8, 112.1, 117.4, 119.3, 121.2,

122.5, 123.3, 124.0, 125.9, 127.3, 128.3, 130.7, 131.0, 132.5,

133.8, 136.6, 137.4, 141.0, 142.5, 153.1, 156.8, 165.5; mass (ES+)

m/z = 456.2 (M⁺+1). Anal. Calcd for C₂₅H₁₈ClN₅O₂C, 65.86; H,

3.98; N, 15.36. Found C, 65.73; H, 3.81; N, 15.60.

4.1.5.32. 3-Chloro-N-(6-{[(4-ﬂuoroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (15b). 95% as a white solid,

4.1.5.37. 3-Chloro-N-[2-methyl-6-({[3-(triﬂuoromethyl)anili-

no]carbonyl}amino)quinolin-4-yl]benzamide (15g).

a yellow solid, mp 236–238 °C; m_max(KBr) 1683 (CO), 3392 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.63 (s, 3H, CH₃), 7.30 (d,

92% as

mp 261–263 °C; m_max(KBr) 1647, 1698 (CO), 3356 (NH) cm^{ꢂ1 1}H

;

NMR (DMSO-d₆, 300 MHz) d = 2.63 (s, 3H, CH₃), 7.11 (t, 2H,

J = 8.8 Hz, ArH), 7.45–7.51 (m, 2H, ArH), 7.58–7.66 (m, 2H, ArH),

7.74 (d, 1H, J = 7.7 Hz, ArH), 7.85–7.95 (m, 2H, ArH), 8.02–8.05

(m, 1H, ArH), 8.12–8.19 (m, 2H, ArH), 8.84 (s, 1H, NH), 9.05 (s,

1H, NH), 9.80 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 25.1,

109.4, 115.5, 115.9, 117.7, 120.4, 120.5, 122.8, 123.3, 128.3,

128.9, 129.4, 132.4, 134.5, 136.3, 137.3, 141.5, 145.2, 153.1,

155.4, 156.8, 160.2, 166.5; mass (FAB+) m/z = 449 (M⁺+1). Anal.

Calcd for C₂₄H₁₈ClFN₄O₂C, 64.22; H, 4.04; N, 12.48. Found C,

64.53; H, 3.96; N, 12.65.

;

1H, J = 7.2 Hz, ArH), 7.50–7.71 (m, 5H, ArH), 7.88 (s, 2H, ArH),

8.00–8.17 (m, 4H, ArH), 9.13 (s, 2H, 2ꢁ NH), 10.57 (s, 1H, NH);

¹³C NMR (DMSO-d₆, 50 MHz) d = 30.3, 111.3, 115.2, 119.8, 122.9,

123.8, 127.5, 127.9, 128.7, 132.4, 133.6, 134.1, 134.7, 135.5,

136.1, 137.7, 139.8, 142.2, 146.1, 146.8, 150.5, 158.3, 162.3,

171.8; mass (FAB+) m/z = 499 (M⁺+1). Anal. Calcd for

C₂₅H₁₈ClF₃N₄O₂C, 60.19; H, 3.64; N, 11.23. Found C, 60.38; H,

4.96; N, 11.02.

4.1.5.38. N-(6-{[(3-Acetylanilino)carbonyl]amino}-2-methyl-

quinolin-4-yl)-3-chlorobenzamide (15i). 86% as a yellow solid,

4.1.5.33. N-(6-{[(4-Bromoanilino)carbonyl]amino}-2-methyl-

quinolin-4-yl)-3-chlorobenzamide (15c). 98% as a white solid,

mp 221–223 °C; m_max(KBr) 1661, 1699 (CO), 3336 (NH) cm^{ꢂ1 1}H

;

mp 214–216 °C; m_max(KBr) 1694, 1706 (CO), 3347 (NH) cm^ꢂ1

;

¹H

NMR (DMSO-d₆, 300 MHz) d = 2.56 (s, 3H, COCH₃), 2.63 (s, 3H,

CH₃), 7.43 (t, 1H, J = 7.8 Hz, ArH), 7.57–7.65 (m, 3H, ArH), 7.71 (d,

2H, J = 5.0 Hz, ArH), 7.87 (s, 2H, ArH), 8.04–8.09 (m, 2H, ArH),

8.17 (d, 2H, J = 7.0 Hz, ArH), 9.19 (s, 1H, NH), 9.25 (s, 1H, NH),

10.23 (s, 1H, NH); mass (FAB+) m/z= 473 (M⁺+1). Anal. Calcd for

C₂₆H₂₁ClN₄O₃C, 66.03; H, 4.48; N, 11.85. Found C, 65.79; H, 4.63;

N, 11.97.

NMR (DMSO-d₆, 300 MHz) d = 2.62 (s, 3H, CH₃), 7.43–7.50 (m,

2H, ArH), 7.57–7.65 (m, 2H, ArH), 7.73 (d, 1H, J = 7.9 Hz, ArH),

7.82–7.90 (m, 2H, ArH), 8.03 (d, 1H, J = 7.6 Hz, ArH), 8.14 (d, 2H,

J = 5.0 Hz, ArH), 8.89 (s, 2H, ArH), 8.95 (s, 1H, NH), 9.09 (s, 1H,

NH), 10.69 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 25.2,

109.6, 113.8, 118.0, 120.7, 122.8, 123.5, 127.2, 128.2, 129.6,

131.1, 132.0, 132.3, 133.8, 136.6, 137.3, 139.4, 141.3, 145.3,

152.8, 153.0, 157.0, 165.2; mass (ES+) m/z = 508.0 (M⁺+1). Anal.

Calcd for C₂₄H₁₈BrClN₄O₂C, 56.55; H, 3.56; N, 10.99. Found C,

56.39; H, 3.82; N, 10.94.

4.1.5.39. 3-Chloro-N-(6-{[(3-chloro-4-methylanilino)carbonyl]-

amino}-2-methylquinolin-4-yl)benzamide (15j). 83% as

white solid, mp 264–266 °C; m_max(KBr) 1689 (CO), 3288 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.29 (s, 3H, CH₃), 2.62 (s,

a

;

4.1.5.34. 3-Chloro-N-(6-{[(3-chloroanilino)carbonyl]amino}-2-

methylquinolin-4-yl)benzamide (15d). 89% as a white solid,

3H, CH₃), 7.16–7.19 (m, 2H, ArH), 7.48–7.61 (m, 3H, ArH), 7.66–

7.77 (m, 3H, ArH) 7.86 (s, 2H, ArH), 8.17 (s, 1H, ArH), 8.27 (s, 1H,

NH), 9.29 (s, 1H, NH), 10.60 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

50 MHz) d = 15.0, 25.1, 109.4, 115.9, 121.2, 121.7, 123.4, 124.1,

126.9, 127.2, 127.5, 139.3, 130.0, 130.4, 131.7, 133.9, 136.8,

137.2, 139.2, 140.7, 145.2, 153.0, 156.9, 166.3; mass (FAB+) m/z=

mp 261–263 °C; m_max(KBr) 1651, 1695 (CO), 3354 (NH) cm^{ꢂ1 1}H

;

NMR (DMSO-d₆, 300 MHz) d = 2.63 (s, 3H, CH₃), 7.01 (d, 1H,

J = 3.1 Hz, ArH), 7.29 (d, 2H, J = 4.7 Hz, ArH), 7.56–7.74 (m, 4H,

ArH), 7.84–7.90 (m, 2H, ArH), 7.98–8.16 (m, 3H, ArH), 8.98 (s, 1H,

216

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

473 (M⁺+1). Anal. Calcd for C₂₅H₂₀Cl₂N₄O₂C, 62.64; H, 4.21; N,

11.69. Found C, 62.52; H, 4.45; N, 11.78.

(M⁺+1). Anal. Calcd for C₂₂H₁₇ClN₄O₃C, 62.79; H, 4.07; N, 13.31.

Found C, 63.04; H, 4.19; N, 13.65.

4.1.5.40. 3-Chloro-N-(6-{[(3-chloro-2-methylanilino)carbonyl]-

4.1.5.46. N-(6-{[(4-Bromoanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-furamide (16c). 89% as a white solid, mp 220–

amino}-2-methylquinolin-4-yl)benzamide (15k). 97% as

a

;

white solid, mp >250 °C; m_max(KBr) 1721 (CO), 3260 (NH) cm^ꢂ1

222 °C; m_max(KBr) 1661 (CO), 3368 (NH) cm^{ꢂ1 1}H NMR (DMSO-

;

¹H NMR (DMSO-d₆, 300 MHz) d = 2.30 (s, 3H, CH₃), 2.62 (s, 3H,

CH₃), 7.16–7.19 (m, 2H, ArH), 7.49–7.62 (m, 3H, ArH), 7.67–7.79

(m, 3H, ArH), 7.87 (s, 2H, ArH), 8.17 (s, 1H, ArH), 8.29 (s, 1H,

NH), 9.32 (s, 1H, NH), 10.81 (s, 1H, NH); mass (ES+) m/z= 479.1

(M⁺+1), 481.1 (M⁺+3). Anal. Calcd for C₂₅H₂₀Cl₂N₄O₂C, 62.64; H,

4.21; N, 11.69. Found C, 62.90; H, 4.47; N, 11.52.

d₆, 300 MHz) d = 2.62 (s, 3H, CH₃), 6.77 (t, 1H, J = 1.6 Hz, ArH),

7.46–7.49 (m, 6H, ArH), 7.58 (s, 1H, ArH), 7.87 (d, 1H, J = 3.1 Hz,

ArH), 8.02 (s, 1H, ArH), 8.08 (s, 1H, ArH), 8.95 (s, 1H, NH), 9.14 (s,

1H, NH), 10.41 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 30.3,

114.5, 118.0, 119.0, 121.2, 122.8, 125.9, 127.8, 128.6, 134.7,

137.2, 142.4, 144.7, 146.0, 150.4, 151.9, 152.7, 158.1, 162.1,

162.4; mass (FAB+) m/z = 465 (M⁺+1). Anal. Calcd for C₂₂H₁₇BrN₄O₃

C, 56.79; H, 3.68; N, 12.04. Found C, 57.13; H, 3.64; N, 12.32.

4.1.5.41. 3-Chloro-N-(6-{[(3,4-dichloroanilino)carbonyl]amino}-

2-methylquinolin-4-yl)benzamide (15l). 80% as a white solid,

mp 249–250 °C; m_max(KBr) 1683 (CO), 3310 (NH) cm^ꢂ1

,

¹H NMR

4.1.5.47. N-(6-{[(3-Cyanoanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-furamide (16f). 87% as a white solid, mp 248–

(DMSO-d₆, 300 MHz) d = 2.64 (s, 3H, CH₃), 7.35 (dd, 1H, J₁=

2.1 Hz, J₂= 8.7 Hz, ArH), 7.52 (d, 1H, J = 8.8 Hz, ArH), 7.60–7.66

(m, 2H, ArH), 7.74 (d, 1H, J = 8.0 Hz, ArH), 7.82–7.91 (m, 3H,

ArH), 8.03 (d, 1H, J = 7.4 Hz, ArH), 8.16 (s, 2H, ArH), 9.08 (s, 1H,

NH), 9.15 (s, 1H, NH), 10.69 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

75 MHz) d = 25.2, 110.0, 117.8, 118.9, 119.9, 122.7, 123.5, 123.8,

127.2, 128.2, 129.6, 131.0, 131.6, 132.3, 133.9, 136.7, 137.0,

140.3, 141.4, 145.4, 152.9, 157.2, 165.3; mass (ES+) m/z = 499.1

(M⁺+1), 501.1 (M⁺+3). Anal. Calcd for C₂₄H₁₇Cl₃N₄O₂C, 57.68; H,

3.43; N, 11.21. Found C, 57.85; H, 3.70; N, 11.27.

250 °C; m_max(KBr) 1659 (CO), 2231 (CN), 3380 (NH) cm^{ꢂ1 1}H

;

NMR (DMSO-d₆, 300 MHz) d = 2.61 (s, 3H, CH₃), 6.65–6.67 (m,

2H, ArH), 7.26 (d, 1H, J = 3.5 Hz, ArH), 7.40–7.51 (m, 3H, ArH),

7.63 (d, 1H, J = 8.3 Hz, ArH), 7.81 (dd, 1H, J₁= 2.1 Hz, J₂= 9.0 Hz,

ArH), 7.93–7.98 (m, 3H, ArH and NH), 8.15 (d, 1H, J = 2.0 Hz,

ArH), 9.05 (s, 1H, NH), 9.25 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

75 MHz) d = 23.5, 107.0, 110.9, 112.0, 119.3, 120.2, 121.3, 122.1,

122.6, 124.7, 128.9, 129.4, 137.3, 139.6, 145.8, 147.4, 151.5,

156.5, 159.7; mass (ES+) m/z = 412.2 (M⁺+1). Anal. Calcd for

C₂₃H₁₇N₅O₃C, 67.15; H, 4.16; N, 17.02. Found C, 67.10; H, 4.43;

N, 17.22.

4.1.5.42. 3-Chloro-N-(6-{[(3,5-dichloroanilino)carbonyl]amino}-

2-methylquinolin-4-yl)benzamide (15m). 91% as a white solid,

mp >250 °C; m_max(KBr) 1691 (CO), 3307 (NH) cm^ꢂ1

,

¹H NMR

4.1.5.48. N-(6-{[(4-Acetylanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-furamide (16h). 88% as a white solid, mp 243–

(DMSO-d₆, 300 MHz) d = 2.62 (s, 3H, CH₃), 7.16 (d, 1H, J = 1.8 Hz,

ArH), 7.49–7.61 (m, 6H, ArH), 7.69–7.72 (m, 2H, ArH), 7.80–7.89

(m, 2H, ArH), 8.20 (s, 1H, NH), 9.12 (s, 1H, NH), 9.16 (s, 1H, NH),

10.77 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 25.3, 110.2,

116.2, 116.6, 121.3, 121.7, 129.6, 129.7, 130.2, 130.6, 131.8,

134.6, 136.8, 137.0, 141.0, 142.8, 157.3, 161.1, 166.5; mass (ES+)

m/z = 499.1 (M⁺+1), 501.1 (M⁺+3). Anal. Calcd for C₂₄H₁₇Cl₃N₄O₂

C, 57.68; H, 3.43; N, 11.21. Found C, 57.85; H, 3.70; N, 11.27.

245 °C; m_max(KBr) 1664 (CO), 3340 (NH) cm^{ꢂ1 1}H NMR (DMSO-

;

d₆, 300 MHz) d = 2.52 (s, 3H, CH₃), 2.63 (s, 3H, CH₃), 6.78 (q, 1H,

J = 1.71 Hz, ArH), 7.48 (d, 1H, J = 3.36 Hz, ArH), 7.59–7.62 (m, 3H,

ArH), 7.84–7.93 (m, 4H, ArH), 8.02 (s, 1H, ArH), 8.09 (d, 1H,

J = 1.4 Hz, ArH), 9.18 (s, 2H, 2ꢁ NH), 10.44 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 50 MHz) d = 25.1, 26.7, 109.6, 112.7, 115.9, 117.8,

122.5, 123.4, 129.6, 130.0, 130.9, 131.1, 136.9, 140.8, 144.3,

144.6, 145.3, 146.6, 147.5, 152.7, 157.0, 157.1, 196.7; mass (ES+)

m/z = 429.2 (M⁺+1). Anal. Calcd for C₂₄H₂₀N₄O₄C, 67.28; H, 4.71;

N, 13.08. Found C, 67.55; H, 4.96; N, 13.34.

4.1.5.43. 3-Chloro-N -(6-{[(3-chloro-4-ﬂuoroanilino)carbonyl]-

amino}-2-methylquinolin-4-yl)benzamide(15n). 92% as

white solid, mp 249–251 °C; m_max(KBr) 1705 (CO), 3277 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.67 (s, 3H, CH₃), 7.34 (s,

a

;

4.1.5.49. N-(6-{[(3-Chloro-4-methylanilino)carbonyl]amino}-2-

methylquinolin-4-yl)-2-furamide (16j). 92% as a white solid,

2H, ArH), 7.61–7.79 (m, 5H, ArH), 7.91 (s, 1H, ArH), 8.10–8.17

(m, 3H, ArH), 9.17 (s, 1H, NH), 9.29 (s, 1H, NH), 10.66 (s, 1H,

NH); mass (FAB+) m/z = 483 (M⁺+1). Anal. Calcd for C₂₄H₁₇

Cl₂FN₄O₂C, 59.64; H, 3.55; N, 11.59. Found C, 59.92; H, 3.80; N,

11.28.

mp 241–243 °C; m_max(KBr) 1705 (CO), 3277 (NH) cm^{ꢂ1 1}H NMR

;

(DMSO-d₆, 300 MHz) d = 2.25 (s, 3H, CH₃), 2.61 (s, 3H, CH₃), 6.75–

6.77 (m, 1H, ArH), 7.20–7.24 (m, 2H, ArH), 7.47 (d, 1H, J = 3.4 Hz,

ArH), 7.57 (s, 1H, ArH), 7.67 (s, 1H, ArH), 7.86 (s, 2H, ArH), 8.01–

8.03 (m, 2H, ArH), 8.82 (s, 1H, NH), 9.07 (s, 1H, NH), 10.41 (s, 1H,

NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 19.3, 25.2, 109.5, 112.8,

116.0, 117.6, 118.7, 122.7, 123.5, 128.9, 129.6, 131.7, 133.6,

137.3, 139.2, 140.8, 145.3, 146.7, 147.6, 153.0, 157.0, 157.2; mass

(ES+) m/z = 435.2 (M⁺+1), 437.2 (M⁺+3). Anal. Calcd for

C₂₃H₁₉ClN₄O₃C, 63.52; H, 4.40; N, 12.88. Found C, 63.76; H, 4.73;

N, 12.65.

4.1.5.44. 3-Chloro-N-(6-{[(4-chloro-3-triﬂuoromethylanilino)-

carbonyl]amino}-2-methylquinolin-4-yl)benzamide (15o). 90%

as a white solid, mp >250 °C; m_max(KBr) 1688 (CO), 3404 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.63 (s, 3H, CH₃), 7.59–

;

7.67 (m, 5H, ArH), 7.85–7.91 (m, 2H, ArH), 8.09–8.12 (m, 4H,

ArH), 9.25 (s, 1H, NH), 9.31 (s, 1H, NH), 10.65 (s, 1H, NH); mass

(ES+) m/z = 533.1 (M⁺+1), 535.1 (M⁺+3). Anal. Calcd for

C₂₅H₁₇Cl₂F₃N₄O₂C, 56.30; H, 3.21; N, 10.51. Found C, 56.38; H,

3.52; N, 10.64.

4.1.5.50. N-(6-{[(3,4-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-furamide (16l). 93% as a white solid, mp

247–249 °C; m_max(KBr) 1678 (CO), 3347 (NH) cm^ꢂ1; 1H NMR

(DMSO-d₆, 300 MHz) d = 2.61 (s, 3H, CH₃), 6.66 (m, 1H, ArH), 7.16

(d, 1H, J = 1.7 Hz, ArH), 7.26 (d, 2H, J = 3.5 Hz, ArH), 7.40 (s, 1H,

ArH), 7.49 (d, 2H, J = 1.7 Hz, ArH), 7.80 (dd, 1H, J₁= 2.1 Hz,

J₂= 9.0 Hz, ArH), 7.92–7.98 (m, 2H, ArH and NH), 8.15 (d, 1H,

J = 2.0 Hz, ArH), 9.07 (s, 1H, NH), 9.28 (s, 1H, NH); mass (ES+) m/

z = 455.3. (M⁺+1), 457.2 (M⁺+3). Anal. Calcd for C₂₂H₁₆Cl₂N₄O₃C,

58.04; H, 3.54; N, 12.31. Found C, 57.79; H, 3.81; N, 12.50.

4.1.5.45. N-(6-{[(4-Chloroanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-furamide (16a). 90% as a white solid, mp 246–

248 °C; m_max(KBr) 1715 (CO), 3361 (NH) cm^{ꢂ1 1}H NMR (DMSO-

;

d₆, 300 MHz) d = 2.62 (s, 3H, CH₃), 6.78 (s, 1H, ArH), 7.32–7.35

(m, 2H, ArH), 7.49–7.52 (m, 3H, ArH), 7.58 (s, 1H, ArH), 7.87 (s,

2H, ArH), 8.02 (s, 1H, ArH), 8.07 (s, 1H, ArH), 8.90 (s, 1H, NH),

9.09 (s, 1H, NH), 10.42 (s, 1H, NH); mass (FAB+) m/z = 421

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

217

4.1.5.51. N-(6-{[(3,5-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-furamide (16m). 91% as a white solid, mp

(s, 1H, NH); mass (FAB+) m/z = 403 (M⁺+1). Anal. Calcd for

C₁₉H₁₆Cl₂N₄O₂C, 56.59; H, 4.00; N, 13.89. Found C, 56.72; H,

4.31; N, 13.62.

246–248 °C; m_max(KBr) 1715 (CO), 3362 (NH) cm^{ꢂ1 1}H NMR

;

(DMSO-d₆, 300 MHz) d = 2.59 (s, 3H, CH₃), 6.65 (t, 1H, J = 1.6 Hz,

ArH), 7.15 (d, 1H, J = 1.1 Hz, ArH), 7.24 (d, 1H, J = 3.2 Hz, ArH),

7.39 (s, 1H, ArH), 7.48 (s, 2H, ArH), 7.78 (d, 1H, J = 9.3 Hz, ArH),

7.91–7.97 (m, 3H, ArH), 8.14 (s, 1H, NH), 9.08 (s, 1H, NH), 9.30 (s,

1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 30.0, 113.6, 118.5,

122.0, 125.8, 126.7, 127.7, 129.1, 129.4, 135.2, 139.7, 143.6,

147.6, 148.8, 150.8, 152.1, 153.7, 157.7, 162.9, 166.1; mass (ES+)

m/z = 455.2 (M⁺+1), 457.2 (M⁺+3). Anal. Calcd for C₂₂H₁₆Cl₂N₄O₃

C, 58. 04; H, 3.54; N, 12.31. Found C, 58.29; H, 3.46; N, 12.67.

4.1.5.57. N-(6-{[(4-Chloroanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24a). 90%

as a white solid, mp 220–221 °C; tR = 20.49 min; m_max(KBr) 1698,

1705 (CO), 3295 (NH) cm^ꢂ1

;

¹H NMR (DMSO-d₆, 200 MHz)

d = 2.16 (s, 3H, CH₃), 2.58 (br s, 7H, CH₃and 2ꢁ CH₂), 3.28 (m,

6H, 3ꢁ CH₂), 7.33 (d, 2H, J = 8.0 Hz, ArH), 7.41–7.49 (m, 2H, ArH),

7.60 (d, 2H, J = 8.0 Hz, ArH), 7.85 (d, 1H, J = 8.0 Hz, ArH), 8.54 (s,

1H, ArH), 8.99 (s, 1H, NH), 9.10 (s, 1H, NH), 10.27 (s, 1H, NH); mass

(ES+) m/z = 467.2 (M⁺+1). Anal. Calcd for C₂₄H₂₇ClN₆O₂C, 61.73; H,

5.83; N, 18.00. Found C, 61.97; H, 6.06; N, 17.85.

4.1.5.52. N-(6-{[(4-Chloro-3-triﬂuoromethylanilino)carbonyl]-

amino}-2-methylquinolin-4-yl)-2-furamide (16o). 88% as

white solid, mp 217–218 °C; m_max(KBr) 1709 (CO), 3392 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.59 (s, 3H, CH₃), 6.63–

a

4.1.5.58. N-(6-{[(4-Fluoromethylanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24b). 90%

as a white solid, mp 216–217 °C; tR = 7.27 min; m_max(KBr) 1635,

;

6.65 (m, 2H, ArH), 7.24 (d, 2H, J = 3.6 Hz, ArH), 7.39 (s, 1H, ArH),

7.54–7.61 (m, 2H, ArH), 7.78 (dd, 1 H, J₁= 2.3 Hz, J₂= 9.2 Hz,

ArH), 7.91 (d, 1H, J = 0.8 Hz, ArH), 8.08 (s, 1H, NH), 8.17 (d, 1H,

J = 2.0 Hz, ArH), 9.18 (s, 1H, NH), 9.26 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 75 MHz) d = 24.8, 108.3, 113.3, 120.5, 122.5, 123.0,

123.6, 123.9, 124.3, 125.1, 127.0, 127.4, 130.1, 132.4, 138.5,

139.6, 143.6, 145.7, 147.0, 148.5, 152.7, 157.7, 160.9; mass (ES+)

m/z = 489.1 (M⁺+1), 491.1 (M⁺+3). Anal. Calcd for C₂₃H₁₆ClF₃N₄O₃

C, 58. 51; H, 3.30; N, 11.46. Found C, 58.29; H, 3.46; N, 12.67.

1708 (CO), 3305 (NH) cm^ꢂ1

;

¹H NMR (DMSO-d₆, 300 MHz)

d = 2.16 (s, 3H, CH₃), 2.58 (br s, 11H, CH₃and 4ꢁ CH₂), 3.27 (s,

2H, CH₂), 7.13 (t, 2 H, J = 8.8 Hz, ArH), 7.44 (d, 1 H, J = 9.0 Hz,

ArH), 7.55–7.60 (m, 2H, ArH), 7.85 (d, 1H, J = 9.0 Hz, ArH), 8.16 (s,

1H, ArH), 8.55 (s, 1H, ArH), 8.87 (s, 1H, NH), 9.05 (s, 1H, NH),

10.26 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 24.2, 44.4,

52.2, 53.4, 60.9, 104.9, 109.4, 114.2, 114.5, 117.7, 119.3, 122.0,

129.0, 135.1, 136.3, 138.7, 143.6, 151.8, 155.9, 168.6; mass (ES+)

m/z = 451.2 (M⁺+1). Anal. Calcd for C₂₄H₂₇FN₆O₂C, 63.98; H, 6.04;

N, 18.65. Found C, 63.72; H, 6.31; N, 18.51.

4.1.5.53. N-(6-{[(4-Chloroanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)acetamide (17a). 92% as a white solid, mp 225–

226 °C; tR = 20.50 min; m_max(KBr) 1631, 1685 (CO), 3298 (NH)

4.1.5.59. N-(6-{[(4-Bromoanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24c). 61%

as a white solid, mp 225–227 °C; tR = 11.27 min; m_max(KBr) 1684,

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.22 (s, 3H, CH₃), 2.56 (s,

;

3H, CH₃), 7.30–7.35 (m, 2H, ArH), 7.45–7.54 (m, 2H, ArH), 7.80–

7.85 (m, 2H, ArH), 8.18 (s, 1H, ArH), 8.86 (s, 1H, ArH), 8.96 (s, 1H,

NH), 8.99 (s, 1H, NH), 10.16 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

75 MHz) d = 24.4, 25.3, 109.5, 114.4, 120.3, 120.9, 123.6, 126.0,

129.1, 129.7, 136.9, 139.0, 139.1, 141.2, 145.3, 152.8, 153.1,

157.1, 169.9; mass (ES+) m/z = 369.1 (M⁺+1), 371.1 (M⁺+3). Anal.

Calcd for C₁₉H₁₇ClN₄O₂C, 61.87; H, 4.65; N, 15.19. Found C,

61.55; H, 4.98; N, 14.86.

1698 (CO), 3300 (NH) cm^ꢂ1

;

¹H NMR (DMSO-d₆, 300 MHz)

d = 2.42 (s, 3 H, CH₃), 2.58 (s, 3H, CH₃), 2.76 (br s, 4H, 2ꢁ CH₂),

2.95 (br s, 4H, 2ꢁ CH₂), 3.33 (s, 2H, CH₂), 7.46–7.55 (m, 5H, ArH),

7.85 (d, 1H, J = 9.0 Hz, ArH), 8.15 (s, 1H, ArH), 8.46 (s, 1H, ArH),

9.53 (s, 1H, NH), 9.71 (s, 1H, NH), 10.23 (s, 1H, NH); ¹³C NMR

(DMSO-d_6,75 MHz) d = 24.2, 43.3, 51.0, 52.8, 60.6, 104.4, 109.3,

112.4, 117.8, 119.3, 121.7, 128.9, 130.7, 136.4, 138.3, 138.6,

143.5, 151.9, 155.8, 168.3; mass (ES+) m/z = 511.2 (M⁺+1), 513.1

(M⁺+3). Anal. Calcd for C₂₄H₂₇BrN₆O₂C, 56.36; H, 5.32; N, 16.43.

Found C, 56.04; H, 5.66; N, 16.09.

4.1.5.54. N-(6-{[(3-Chloro-4-methylanilino)carbonyl]amino}-2-

methylquinolin-4-yl)acetamide (17j). 68% as a white solid, mp

213–214 °C; tR = 15.52 min;

m_max(KBr) 1645, 1676 (CO), 3285 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.24 (s, 3H, CH₃), 2.27 (s,

;

4.1.5.60. N-(6-{[(3-Cloromethylanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24d). 81%

as a white solid, mp 196–198 °C; m_max(KBr) 1702 (CO), 3303 (NH)

cm^ꢂ1, ¹H NMR (DMSO-d₆, 300 MHz) d = 2.20 (s, 3H, CH₃), 2.58 (br s,

11H, 2ꢁ CH₃and 4ꢁ CH₂), 3.28 (s, 2H, CH₂), 7.04 (dd, 1H,

J₁= 1.8 Hz, J₂= 6.9 Hz, ArH), 7.26–7.34 (m, 2H, ArH), 7.43 (dd, 1H,

J₁= 1.8 Hz, J₂= 8.9 Hz, ArH), 7.86 (d, 1H, J = 8.9 Hz, ArH), 7.94 (s,

1H, ArH), 8.18 (s, 1H, ArH), 8.59 (d, 1H, J = 1.5 Hz, ArH), 9.06 (s,

1H, NH), 9.15 (s, 1H, NH), 10.29 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

50 MHz) d = 25.9, 45.9, 53.6, 55.0, 62.5, 106.5, 110.9, 117.6, 118.6,

119.3, 122.5, 123.6, 130.7, 131.2, 134.2, 137.8, 140.4, 142.0,

145.3, 153.3, 157.7, 170.2; mass (ES+) m/z = 467.2 (M⁺+1), 469.1

(M⁺+3). Anal. Calcd for C₂₄H₂₇ClN₆O₂C, 61.73; H, 5.83; N, 18.00.

Found C, 61.68; H, 6.15; N, 17.78.

3H, CH₃), 2.57 (s, 3H, CH₃), 7.25 (s, 2 H, ArH), 7.75–7.85 (m, 4H,

ArH), 8.18 (s, 1H, ArH), 8.91 (s, 1H, NH), 8.98 (s, 1H, NH), 10.15

(s, 1H, NH); mass (ES+) m/z = 383.2 (M⁺+1). Anal. Calcd for

C₂₀H₁₉ClN₄O₂C, 62.74; H, 5.00; N, 14.63. Found C, 62.54; H, 4.89;

N, 14.80.

4.1.5.55. N-(6-{[(4-Acetylanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)acetamide (17h). 78% as a white solid, mp 230–

231 °C; tR = 13.79 min; m_max(KBr) 1663, 1708 (CO), 3339 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz) d = 2.09 (s, 3H, CH₃), 2.25 (s,

;

3H, CH₃), 2.58 (s, 3H, CH₃), 7.62 (t, 2H, J = 7.1 Hz, ArH), 7.80–7.95

(m, 4H, ArH), 8.22 (s, 1H, ArH), 9.10 (s, 1H, ArH), 9.26 (s, 2H, 2ꢁ

NH), 10.20 (s, 1H, NH); mass (ES+) m/z = 377.1 (M⁺+1). Anal. Calcd

for C₂₁H₂₀N₄O₃C, 67.01; H, 5.36; N, 14.88. Found C, 66.73; H, 5.52;

N, 14.57.

4.1.5.61. N-(6-{[(3-Fluoromethylanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24e). 84%

as a light green solid, mp 170–172 °C; m_max(KBr) 1651, 1707 (CO),

4.1.5.56. N-(6-{[(3,5-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)acetamide (17m). 75% as a yellow solid, mp

219–220 °C; tR = 14.57 min; m_max(KBr) 1682 (CO), 3265 (NH)

3366 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.18 (s, 3H,

,

CH₃), 2.58–2.62 (m, 11H, CH₃and 4ꢁ CH₂), 3.27 (s, 2H, CH₂), 6.77

(dt, 1H, J₁= 1.8 Hz, J₂= 8.2 Hz, ArH), 7.20–7.33 (m, 2H, ArH), 7.49

(dd, 1H, J₁= 1.7 Hz, J₂= 9.0 Hz, ArH), 7.71–7.75 (m, 1H, ArH), 7.84

(d, 1H, J = 8.9 Hz, ArH), 8.18 (s, 1H, ArH), 8.60 (d, 1H, J = 1.5 Hz,

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.24 (s, 3H, CH₃), 2.58 (s,

;

3H, CH₃), 7.17 (s, 1H, ArH), 7.58 (s, 2H, ArH), 7.78–7.83 (m, 3H,

ArH), 8.19 (s, 1H, ArH), 9.12 (s, 1H, NH), 9.16 (s, 1H, NH), 10.14

218

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

ArH), 9.84 (s, 1H, NH), 9.91 (s, 1H, NH), 10.26 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 50 MHz) d = 25.5, 27.2, 45.7, 53.9, 54.7, 62.2, 69.7,

106.4, 110.6, 118.0, 119.0, 122.5, 123.4, 129.5, 130.3, 137.4,

137.9, 140.0, 144.9, 153.0, 157.3, 169.8, 198.1; mass (ES+) m/

z = 451.2 (M⁺+1). Anal. Calcd for C₂₄H₂₇FN₆O₂C, 63.98; H, 6.04;

N, 18.65. Found C, 63.72; H, 6.30; N, 18.68.

s, 4H, 2ꢁ CH₂), 3.28–3.30 (m, 4H, 2ꢁ CH₂), 3.48 (s, 2H, CH₂), 7.24

(d, 1H, J = 4.2 Hz, ArH), 7.44 (d, 1H, J = 7.3 Hz, ArH), 7.70 (d, 1H,

J = 1.4 Hz, ArH), 7.88 (d, 1H, J = 8.9 Hz, ArH), 7.97 (s, 1H, ArH),

8.21 (s, 1H, ArH), 8.62 (s, 1H, ArH), 8.94 (s, 1H, NH), 9.11 (s, 1H,

NH), 10.32 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 18.0,

24.2, 44.6, 52.2, 53.4, 61.0, 104.7, 109.2, 116.1, 116.3, 117.5,

117.6, 122.0, 127.6, 129.0, 130.2, 132.3, 132.4, 136.2, 137.9,

138.7, 143.6, 151.5, 156.0, 168.6; mass (FAB+) m/z = 481 (M⁺+1).

Anal. Calcd for C₂₅H₂₉ClN₆O₂C, 62.43; H, 6.08; N, 17.47. Found C,

62.79; H, 6.10; N, 17.64.

4.1.5.62. N-(6-{[(3-Cyanoanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24f). 57% as

a white solid, mp 169–170 °C; tR = 7.69 min; m_max(KBr) 1695 (CO),

2230 (CN), 3397 (NH) cm^ꢂ1; ¹H NMR (DMSO-d₆, 200 MHz) d = 2.25

(s, 3H, CH₃), 2.64 (s, 3H, CH₃), 2.69 (s, 8H, 4ꢁ CH₂), 3.34 (s, 2H, CH₂),

7.47–7.61 (m, 3H, ArH), 7.70 (d, 1H, J = 7.6 Hz, ArH), 7.93 (d, 1H,

J = 9.0 Hz, ArH), 8.26–8.37 (m, 2H, ArH), 8.67 (s, 1H, ArH), 9.28 (s,

1H, NH), 9.32 (s, 1H, NH), 10.35 (s, 1H, NH); mass (ES+) m/

z = 458.2 (M⁺+1). Anal. Calcd for C₂₅H₂₇N₇O₂C, 65.63; H, 5.95; N,

21.43. Found C, 65.42; H, 6.06; N, 21.22.

4.1.5.67. N-(6-{[(3-Chloro-2-methylanilino)carbonyl]amino}-

2-methylquinolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide

(24k). 74% as a white solid, mp 238–240 °C; m_max(KBr) 1638, 1714

(CO), 3284 (NH) cm^ꢂ1, ¹H NMR (DMSO-d₆, 300 MHz) d = 2.09 (s, 3H,

CH₃), 2.34 (s, 3H, CH₃), 2.54–2.58 (m, 11H, 4ꢁ CH₂and CH₃), 3.26 (s,

2H, CH₂), 7.17 (d, 2H, J = 4.5 Hz, ArH), 7.44 (dd, 1H, J₁= 1.4 Hz,

J₂= 8.9 Hz, ArH), 7.85–7.92 (m, 2H, ArH), 8.17 (s, 1H, ArH), 8.28 (s,

1H, ArH), 8.58 (s, 1H, NH), 9.40 (s, 1H, NH), 10.24 (s, 1H, NH); ¹³C

NMR (DMSO-d₆, 50 MHz) d = 14.1, 25.5, 45.6, 53.5, 54.6, 62.3,

113.2, 116.7, 121.7, 124.3, 127.3, 127.4, 128.3, 128.7, 130.7, 134.0,

134.7, 134.9, 139.3, 140.0, 148.1, 153.3, 169.9; mass (ES+) m/

z = 481.2 (M⁺+1), 483.2 (M⁺+3). Anal. Calcd for C₂₅H₂₉ClN₆O₂C,

62.43; H, 6.08; N, 17.47. Found C, 62.75; H, 6.10; N, 17.69.

4.1.5.63. N-[2-Methyl-6-({[3-(triﬂuoromethyl)anilino]carbonyl}-

amino)quinolin-4-yl]-2-(4-methylpiperazin-1-yl)acetamide

(24g). 76% as an off white solid, mp 148–149 °C; tR = 11.32 min;

m_max(KBr) 1710 (CO), 3301 (NH) cm^ꢂ1

;

¹H NMR (DMSO-d₆,

300 MHz) d = 2.08 (s, 3H, CH₃), 2.57–2.61 (m, 7H, CH₃and 2ꢁ

CH₂), 3.26 (s, 2H, CH₂), 3.45 (s, 4H, 2ꢁ CH₂), 7.32 (d, 1H,

J = 7.5 Hz, ArH), 7.43–7.61 (m, 3H, ArH), 7.86 (d, 1H, J = 8.9 Hz,

ArH), 8.18 (d, 2H, J = 9.6 Hz, ArH), 8.56 (d, 1H, J = 1.7 Hz, ArH),

9.19 (s, 1H, NH), 9.21 (s, 1H, NH), 10.29 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 75 MHz) d = 24.1, 44.2, 52.0, 53.3, 60.8, 105.0, 109.2,

113.5, 117.6, 121.1, 122.1, 128.6, 129.0, 136.0, 138.7, 139.6,

143.6, 151.6, 156.1, 168.6; mass (ES+) m/z = 501.2 (M⁺+1). Anal.

Calcd for C₂₅H₂₇F₃N₆O₂C, 59.99; H, 5.44; N, 16.79. Found C,

59.98; H, 5.73; N, 16.83.

4.1.5.68. N-(6-{[(3,4-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-(4-isopropylpiperazin-1-yl)acetamide (24l). 74%

as a white solid, mp 227–229 °C; m_max(KBr) 1686, 1709 (CO), 3291

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.17 (s, 3H, CH₃), 2.58

;

(s, 3H, CH₃), 2.61 (s, 8H, 4ꢁ CH₂), 3.28 (s, 2H, CH₂), 7.32 (dd, 1H,

J₁= 3.0 Hz, J₂= 9.0 Hz, ArH), 7.44 (dd, 1H, J₁= 3.0 Hz, J₂= 9.0 Hz, ArH),

7.53 (d, 1H, J = 9.0 Hz, ArH), 7.87 (d, 1H, J = 9.0 Hz, ArH), 8.12 (d, 1H,

J = 3.0 Hz, ArH), 8.18 (s, 1H, ArH), 8.57 (d, 1H, J = 3.0 Hz, ArH), 9.12

(s, 1H, NH), 9.15 (s, 1H, NH), 10.28 (s, 1H, NH); mass (ES+) m/

z = 501.2 (M⁺+1), 503.1 (M⁺+3). Anal. Calcd for C₂₄H₂₆Cl₂N₆O₂C,

57.49; H, 5.23; N, 16.76. Found C, 57.19; H, 5.50; N, 16.51.

4.1.5.64. N-(6-{[(4-Acetylanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24h). 75% as

a white solid, mp 226–228 °C; m_max(KBr) 1658, 1707 (CO), 3338

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.19 (s, 3H, CH₃),

;

2.51 (s, 3H, CH₃), 2.59–2.62 (m, 11H, CH₃and 4ꢁ CH₂), 3.29 (s,

2H, CH₂), 7.47 (dd, 1H, J₁= 1.9 Hz, J₂= 8.9 Hz, ArH), 7.70 (d, 2H,

J = 8.7 Hz, ArH), 7.85–7.93 (m, 3H, ArH), 8.17 (s, 1H, ArH), 8.56 (d,

1H, J = 1.9 Hz, ArH), 9.20 (s, 1H, NH), 9.28 (s, 1H, NH), 10.28 (s,

1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 24.2, 25.5, 44.5, 52.2,

53.4, 61.0, 105.2, 109.4, 116.5, 117.7, 122.0, 128.7, 129.0, 129.8,

135.9, 138.8, 143.4, 143.7, 151.3, 156.1, 168.5, 195.5; mass (ES+)

m/z = 475.2 (M⁺+1). Anal. Calcd for C₂₆H₃₀N₆O₃C, 65.80; H, 6.37;

N, 17.71. Found C, 65.57; H, 6.52; N, 17.43.

4.1.5.69. N-(6-{[(3,5-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24m). 65%

as a white solid, mp 160–162 °C; tR = 15.46 min; m_max(KBr) 1698,

1719 (CO), 3353 (NH) cm^ꢂ1; ¹H NMR (DMSO-d₆, 300 MHz) d = 2.19

(s, 3H, CH₃), 2.57 (s, 3 H, CH₃), 2.63 (s, 8H, 4ꢁ CH₂), 3.26 (s, 2H,

CH₂), 7.15 (s, 1H, ArH), 7.43 (d, 1H, J = 6.0 Hz, ArH), 7.64 (s, 2H,

ArH), 7.86 (d, 1H, J = 9.0 Hz ArH), 8.18 (s, 1H, ArH), 8.56 (s, 1H,

ArH), 9.20 (s, 1H, NH), 9.24 (s, 1H, NH), 10.26 (s, 1H, NH); ¹³C

NMR (DMSO-d_6,75 MHz) d = 24.2, 44.4, 52.1, 53.4, 60.9, 78.3,

105.0, 109.1, 115.6, 117.5, 120.2, 122.0, 129.0, 133.3, 135.8,

138.7, 141.3, 143.7, 151.3, 156.2, 168.5; mass (ES+) m/z = 501.2

(M⁺+1), 503.1 (M⁺+3). Anal. Calcd for C₂₄H₂₆Cl₂N₆O₂C, 57.49; H,

5.23; N, 16.76. Found C, 57.31; H, 5.16; N, 16.83.

4.1.5.65. N-(6-{[(3-Acetylanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide (24i). 81% as

a white solid, mp 235–237 °C; m_max(KBr) 1676, 1709 (CO), 3247

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 2.08 (s, 3H, CH₃),

,

2.58 (br s, 14H, 2ꢁ CH₃and 4ꢁ CH₂), 3.28 (s, 2H, CH₂), 7.42–7.49

(m, 2H, ArH), 7.61 (d, 1H, J = 7.7 Hz, ArH), 7.82–7.88 (m, 2H,

ArH), 8.11 (s, 1H, ArH), 8.16 (s, 1H, ArH), 8.55 (d, 1H, J = 1.1 Hz,

ArH), 9.04 (s, 1H, NH), 9.07 (s, 1H, NH), 10.29 (s, 1H, NH); ¹³C

NMR (DMSO-d₆, 75 MHz) d = 25.5, 27.2, 45.7, 53.5, 54.7, 62.2,

69.7, 106.4, 110.6, 118.0, 119.0, 122.5, 123.4, 129.5, 130.3, 137.4,

137.9, 140.0, 140.5, 144.9, 153.0, 157.3, 169.8, 198.1; mass (ES+)

m/z = 475.2 (M⁺+1). Anal. Calcd for C₂₆H₃₀N₆O₃C, 65.80; H, 6.37;

N, 17.71. Found C, 65.97; H, 6.51; N, 17.73.

4.1.5.70. N-(6-{[(4-Chloro-3-triﬂuoromethylanilino)carbonyl]-

amino}-2-methylquinolin-4-yl)-2-(4-methylpiperazin-1-yl)ace-

tamide (24o). 62% as a white solid, mp 185–186 °C; m_max(KBr)

1684, 1718 (CO), 3281 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 200 MHz)

;

d = 2.06 (s, 3H, CH₃), 2.59 (br s, 7H, CH₃and 2ꢁ CH₂), 3.28–3.31

(m, 4H, 2ꢁ CH₂), 3.46 (s, 2H, CH₂), 7.46 (d, 1H, J = 9.0 Hz, ArH),

760–7.63 (m, 2H, ArH), 7.87 (d, 1H, J = 9.0 Hz, ArH), 8.20 (s, 1H,

ArH), 8.32 (d, 1H, J = 1.3 Hz, ArH), 8.57 (s, 1H, ArH), 9.28 (s, 1H,

NH), 9.35 (s, 1H, NH), 10.32 (s, 1H, NH); mass (ES+) m/z = 535.1

(M⁺+1), 537.1 (M⁺+3). Anal. Calcd for C₂₅H₂₆ClF₃N₆O₂C, 56.13; H,

4.90; N, 15.71. Found C, 56.05; H, 4.77; N, 15.79.

4.1.5.66. N-(6-{[(3-Chloro-4-methylanilino)carbonyl]amino}-

2-methylquinolin-4-yl)-2-(4-methylpiperazin-1-yl)acetamide

(24j). 98% as a white solid, mp 217–219 °C; tR = 22.65 min; m_max

4.1.5.71. N-[2-Methyl-6-({[3-(triﬂuoromethyl)anilino]carbonyl}-

amino)quinolin-4-yl]-2-(4-ethylpiperazin-1-yl)acetamide (25g).

79% as a white solid, mp 139–141 °C; m_max(KBr) 1684, 1717 (CO),

(KBr) 1685 (CO), 3293 (NH) cm^{ꢂ1 1}H NMR (DMSO-d₆, 200 MHz)

;

d = 2.20 (s, 3H, CH₃), 2.28 (s, 3H, CH₃), 2.60 (s, 3H, CH₃), 2.64 (br

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

219

3338 (NH) cm^ꢂ1

;

¹H NMR (DMSO-d₆, 300 MHz) d = 0.84 (t, 3H,

8.22 (s, 1H, ArH), 8.63 (d, 1H, J = 1.7 Hz, ArH), 8.96 (s, 1H, NH),

9.08 (s, 1H, NH), 10.46 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz)

d = 22.8, 25.8, 45.9, 53.7, 54.9, 62.7, 105.5, 106.0, 110.8, 114.7,

119.3, 123.8, 130.4, 130.7, 130.9, 138.9, 140.3, 145.1, 154.0,

157.3, 160.9, 167.8, 170.3; mass (ES+) m/z = 452.2 (M⁺+1), 454.1

(M⁺+3). Anal. Calcd for C₂₄H₂₆ClN₅O₂C, 63.78; H, 5.80; N, 15.50.

Found C, 63.72; H, 6.04; N, 15.82.

J = 7.2 Hz, CH₂CH₃), 2.21 (q, 2H, J = 7.2 Hz, CH₂CH₃), 2.54–2.58 (m,

11H, CH₃and 4ꢁ CH₂), 3.27 (s, 2H, CH₂), 7.32 (d, 1H, J = 7.7 Hz,

ArH), 7.44–7.54 (m, 2H, ArH), 7.64 (d, 1H, J = 8.3 Hz, ArH), 7.86

(d, 1H, J = 9.0 Hz, ArH), 8.15 (d, 2H, J = 10.7 Hz, ArH), 8.56 (d, 1H,

J = 1.8 Hz, ArH), 9.22 (s, 1H, NH), 9.23 (s, 1H, NH), 10.32 (s, 1H,

NH); ¹³C NMR (DMSO-d₆, 75 MHz) d = 11.1, 24.2, 50.3, 51.2, 52.2,

60.9, 98.7, 109.2, 117.6, 122.1, 129.0, 136.0, 138.7, 139.6, 143.7,

151.7, 156.1, 168.5; mass (ES+) m/z = 515.3 (M⁺+1). Anal. Calcd

for C₂₆H₂₉F₃N₆O₂C, 60.69; H, 5.68; N, 16.33. Found C, 60.93; H,

5.54; N, 16.48.

4.1.5.76. N-[2-Methyl-6-({[3-(triﬂuoromethyl)anilino]carbonyl}-

amino)quinolin-4-yl)-2-piperidin-1-ylacetamide (26g). 91% as

a white solid, mp 219–220 °C; tR = 17.26 min; m_max(KBr) 1668,

;

1718 (CO), 3367 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz)

4.1.5.72. N-(6-{[(3-Chloro-4-methylanilino)carbonyl]amino}-2-

methylquinolin-4-yl)-2-(4-ethylpiperazin-1-yl)acetamide (25j).

88% as a white solid, mp 213–215 °C; m_max(KBr) 1674, 1710 (CO),

d = 1.42 (br s, 2H, CH₂), 1.80 (br s, 4H, 2ꢁ CH₂), 2.57 (s, 7H, CH₃

and 2ꢁ CH₂), 3.21 (s, 2H, CH₂), 7.32 (d, 1H, J = 6.6 Hz, ArH), 7.40

(dd, 1H, J₁= 2.0 Hz, J₂= 9.0 Hz, ArH), 7.50–7.52 (m, 2H, ArH), 7.85

(d, 1H, J = 9.0 Hz, ArH), 8.24 (s, 2H, ArH), 8.66 (d, 1H, J = 1.9 Hz,

ArH), 9.18 (s, 1H, NH), 9.19 (s, 1H, NH), 10.48 (s, 1H, NH); mass

(ES+) m/z = 486.3 (M⁺+1). Anal. Calcd for C₂₅H₂₆F₃N₅O₂C, 61.85;

H, 5.40; N, 14.42. Found C, 61.59; H, 5.64; N, 14.57.

3283 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d_6,300 MHz) d = 0.91 (t, 3H,

;

J = 7.1 Hz, CH₂CH₃), 2.26–2.35 (m, 5H, CH₃, and CH₂CH₃), 2.58 (s,

3H, CH₃), 2.64 (br s, 8H, 4ꢁ CH₂), 3.27 (s, 2H, CH₂), 7.22 (s, 2H,

ArH), 7.42 (dd, 1H, J₁= 1.9 Hz, J₂= 9.0 Hz, ArH), 7.85 (d, 2H,

J = 8.6 Hz, ArH), 8.17 (s, 1H, ArH), 8.56 (s, 1H, J = 1.8 Hz, ArH),

8.92 (s, 1H, NH), 9.09 (s, 1H, NH), 10.29 (s, 1H, NH); ¹³C NMR

(DMSO-d₆, 75 MHz) d = 11.3, 18.0, 24.2, 29.8, 50.4, 51.2, 52.3,

61.0, 104.8, 109.1, 116.3, 117.5, 117.6, 122.0, 127.6, 129.0, 130.2,

132.4, 136.1, 137.9, 138.7, 143.6, 151.6, 156.0, 168.5; mass (ES+)

m/z = 495.4 (M⁺+1), 497.2 (M⁺+3). Anal. Calcd for C₂₆H₃₁ClN₅O₂C,

63.08; H, 6.31; N, 16.98. Found C, 59.97; H, 6.64; N, 16.92.

4.1.5.77. N-(6-{[(3-Chloro-4-methylanilino)carbonyl]amino}-2-

methylquinolin-4-yl)-2-piperidin-1-ylacetamide (26i). 82% as

a white solid, mp 265–266 °C; m_max(KBr) 1682 (CO), 3287 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 1.51 (br s, 2H, CH₂), 1.85

,

(br s, 4H, 2ꢁ CH₂), 2.27 (s, 3H, CH₃), 2.58 (s, 7H, CH₃and 2ꢁ

CH₂), 3.22 (s, 2H, CH₂), 7.13 (dd, 1H, J₁= 1.8 Hz, J₂= 8.3 Hz, ArH),

7.25 (d, 1H, J = 8.2 Hz, ArH), 7.38–7.41 (m, 1H, ArH), 7.85 (d, 1 H,

J = 8.9 Hz, ArH), 7.95 (d, 1H, J = 1.7 Hz, ArH), 8.25 (s, 1H, ArH),

8.70 (s, 1H, ArH), 8.91 (s, 1H, NH), 9.08 (s, 1H, NH), 10.48 (s, 1H,

NH); mass (ES+) m/z = 466.1 (M⁺+1), 468.1 (M⁺+3). Anal. Calcd for

C₂₅H₂₈ClN₅O₂C, 64.44; H, 6.06; N, 15.03. Found C, 64.19; H, 6.33;

N, 14.97.

4.1.5.73. N-(6-{[(3,4-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-(4-ethylpiperazin-1-yl)acetamide (25l). 61%

as a white solid, mp 190–192 °C; tR = 12.35 min; m_max(KBr) 1710

(CO), 3353 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 0.90 (t,

;

3H, J = 7.1 Hz, CH₂CH₃), 2.29 (q, 2H, J = 7.1 Hz, CH₂CH₃), 2.58 (s,

3H, CH₃), 2.64 (br s, 4H, 4ꢁ CH₂), 3.17 (s, 4H, 4ꢁ CH₂), 3.27 (s,

2H, CH₂), 7.33 (dd, 1H, J₁= 2.4 Hz, J₂= 8.8 Hz, ArH), 7.44 (dd, 1H,

J₁= 1.7 Hz, J₂= 9.0 Hz, ArH), 7.51 (d, 1H, J = 8.7 Hz, ArH), 7.86 (d,

1H, J = 8.9 Hz, ArH), 8.05 (d, 1H, J = 2.3 Hz, ArH), 8.17 (s, 1H, ArH),

8.54 (d, 1H, J = 1.5 Hz, ArH), 9.17 (s, 1H, NH), 9.21 (s, 1H, NH),

10.30 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 12.4, 25.4,

51.6, 52.4, 53.4, 62.1, 110.3, 119.0, 120.0, 123.3, 123.7, 130.2,

130.8, 131.5, 137.1, 139.9, 140.1, 144.8, 152.7, 157.4, 169.7; mass

(ES+) m/z = 515.4 (M⁺+1), 517.2 (M⁺+3). Anal. Calcd for

C₂₅H₂₈Cl₂N₆O₂C, 58.26; H, 5.48; N, 16.30. Found C, 58.31; H,

5.53; N, 16.47.

4.1.5.78. N-(6-{[(3,4-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-piperidin-1-ylacetamide (26l). 89% as

white solid, mp 215–216 °C; m_max(KBr) 1670, 1716 (CO), 3361

(NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 1.49 (br s, 2H, CH₂),

a

;

1.83 (br s, 4H, 2ꢁ CH₂), 2.57 (s, 7H, CH₃and 2ꢁ CH₂), 3.21 (s, 2H,

CH₂), 7.22 (dd, 1H, J₁= 2.5 Hz, J₂= 8.8 Hz, ArH), 7.40 (dd, 1H,

J₁= 2.0 Hz, J₂= 9.0 Hz, ArH), 7.52 (d, 1H, J = 8.7 Hz, ArH), 7.84 (d,

1H, J = 8.9 Hz, ArH), 8.16 (d, 1H, J = 2.4 Hz, ArH), 8.24 (s, 1H, ArH),

8.68 (d, 1H, J = 1.9 Hz, ArH), 9.16 (s, 1H, NH), 9.20 (s, 1H, NH),

10.48 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 22.7, 24.2,

24.5, 53.6, 61.8, 104.5, 108.4, 117.2, 117.4, 118.2, 121.8, 122.4,

129.1, 129.7, 130.4, 136.0, 138.6, 139.0, 143.6, 151.5, 156.2,

168.9; mass (ES+) m/z = 486.4 (M⁺+1), 488.1 (M⁺+3). Anal. Calcd

for C₂₄H₂₅Cl₂N₅O₂C, 59.26; H, 5.18; N, 14.40. Found C, 59.04; H,

5.35; N, 14.72.

4.1.5.74. N-(6-{[(3,5-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-(4-ethylpiperazin-1-yl)acetamide (25m). 64%

as a white solid, mp 186–188 °C; m_max(KBr) 1699, 1705 (CO),

3282 (NH) cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 0.91 (t, 3H,

;

J = 6.9 Hz, CH₂CH₃), 2.31 (q, 2H, J = 7.0 Hz, CH₂CH₃), 2.58 (s, 3H,

CH₃), 2.64 (br s, 8H, 4ꢁ CH₂), 3.27 (s, 2H, CH₂), 7.17 (s, 1H, ArH),

7.44 (d, 1H, J = 8.6 Hz, ArH), 7.63 (s, 2H, ArH), 7.86 (d, 1H,

J = 8.8 Hz, ArH), 8.18 (s, 1H, ArH), 8.55 (s, 1H, ArH), 9.25 (s, 1H,

NH), 9.31 (s, 1H, NH), 10.30 (s, 1H, NH); ¹³C NMR (DMSO-d₆,

50 MHz) d = 12.5, 25.4, 51.6, 52.4, 53.3, 62.1, 106.4, 110.3, 116.9,

118.7, 121.4, 123.3, 130.2, 134.5, 137.0, 139.9, 142.5, 152.6,

157.4, 169.7; mass (ES+) m/z = 515.3 (M⁺+1), 517.2 (M⁺+3). Anal.

Calcd for C₂₅H₂₈Cl₂N₆O₂C, 58.26; H, 5.48; N, 16.30. Found C,

58.40; H, 5.61; N, 16.24.

4.1.5.79. N-(6-{[(3,5-Dichloroanilino)carbonyl]amino}-2-meth-

ylquinolin-4-yl)-2-piperidin-1-ylacetamide (26m).

white solid, mp 218–219 °C; _max(KBr) 1680, 1720 (CO), 3255 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 1.52 (s, 2H, CH₂), 1.85 (s,

89% as a

m

;

4H, 2ꢁ CH₂), 2.59 (s, 7H, CH₃and 2ꢁ CH₂), 3.35 (s, 2H, CH₂), 7.19

(s, 1H, ArH), 7.42 (dd, 1H, J₁= 1.6 Hz, J₂= 9.0 Hz, ArH), 7.64 (d,

2H, J = 1.5 Hz, ArH), 7.86 (d, 1H, J = 9.0 Hz, ArH), 8.26 (s, 1H, ArH),

8.71 (s, 1H, ArH), 9.21 (s, 1H, NH), 9.29 (s, 1H, NH), 10.49 (s, 1H,

NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 24.4, 25.9, 26.2, 55.3, 63.5,

99.0, 104.8, 106.3, 110.1, 117.0, 118.8, 121.9, 123.6, 130.8, 135.0,

137.6, 140.4, 143.1, 145.3, 153.1, 157.9, 170.6; mass (ES+) m/

z = 486.1 (M⁺+1), 488.1 (M⁺+3). Anal. Calcd for C₂₄H₂₅Cl₂N₅O₂C,

59.26; H, 5.18; N, 14.40. Found C, 59.12; H, 5.07; N, 14.61.

4.1.5.75. N-(6-{[(4-Chloroanilino)carbonyl]amino}-2-methylqu-

inolin-4-yl)-2-piperidin-1-ylacetamide (26a). 83% as a white

solid, mp 249–250 °C; m_max(KBr) 1672, 1716 (CO), 3361 (NH)

cm^ꢂ^{1 1}H NMR (DMSO-d₆, 300 MHz) d = 1.46 (br s, 2H, CH₂), 1.82

,

(br s, 4H, 2ꢁ CH₂), 2.58 (s, 7H, CH₃and 2ꢁ CH₂), 3.22 (s, 2H,

CH₂), 7.34 (d, 2H, J = 8.8 Hz, ArH), 7.44 (dd, 1H, J₁= 1.9 Hz, J₂= 9.0

Hz, ArH), 7.57 (d, 2H, J = 8.9 Hz, ArH), 7.85 (d, 1H, J = 9.0 Hz, ArH),

4.1.5.80. N-[6-({[3-Chloro-4-(triﬂuoromethyl)anilino]carbonyl}-

amino)-2-methylquinolin-4-yl)-2-piperidin-1-ylacetamide (26o).

86% as a white solid, mp 225–226 °C; m_max(KBr) 1682, 1728 (CO),

220

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

3353 (NH) cm^ꢂ1

;

¹H NMR (DMSO-d₆, 300 MHz) d = 1.41 (br s, 2H,

5.2. Cytotoxicity assay

CH₂), 1.77 (br s, 4H, 2ꢁ CH₂), 2.59 (s, 7H, CH₃and 2ꢁ CH₂), 3.37

(s, 2H, CH₂), 7.45 (dd, 1H, J₁= 1.5 Hz, J₂= 9.0 Hz, ArH), 7.58–7.65

(m, 2H, ArH), 7.87 (d, 2H, J = 9.0 Hz, ArH), 8.23 (s, 1H, ArH), 8.30

(t, 1H, J = 3.1 Hz, ArH), 9.23 (s, 1H, NH), 9.30 (s, 1H, NH), 10.47 (s,

1H, NH); ¹³C NMR (DMSO-d₆, 50 MHz) d = 24.3, 25.9, 26.0, 26.1,

55.3, 63.4, 67.9, 106.4, 110.4, 117.4, 119.0, 123.4, 123.7, 123.9,

130.8, 132.8, 137.6, 140.1, 140.4, 145.3, 153.3, 157.9, 170.6; mass

(ES+) m/z = 520.1 (M⁺+1), 522.1 (M⁺+3). Anal. Calcd for

C₂₅H₂₅ClFN₅O₂C, 57.75; H, 4.85; N, 13.47. Found C, 57.94; H,

5.02; N, 13.30.

Cytotoxicity of the compounds was carried out with Vero cell

line (C1008; Monkey kidney ﬁbroblast) following the method of

Mosmann with certain modiﬁcations.¹¹The cells were incubated

with serially diluted compounds for 72 h. The highest concentra-

tion of compounds was remained to be 100 lg/mL. MTT was used

as reagent for the detection of cytotoxicity. 50% cytotoxic concen-

tration (CC₅₀) values represented the concentration of compound

required to kill 50% of the ﬁbroblast cells.

Selectivity Index (SI): It was calculated as

SI = CC₅₀/IC₅₀

.

5. Materials and methods

5.3 In vivo antimalarial assay

5.1. In vitro antimalarial assay

Swiss mice (25 1 g) of either sex were inoculated with 1 ꢁ 10⁶

P. yoelii nigeriensis MDR/P. yoelii N67 chloroquine resistant parasit-

ized cells on day zero. A group of ﬁve mice was administered aque-

ous suspension of the test compounds at 50 mg/kg or 100 mg/kg

dose from day zero to three via oral route; while another ﬁve mice

were administered the vehicle alone. Thin blood smears from the

tail vein of treated as well as control mice were observed on day

4, 7, 14, 21 and 28 days to record the degree of parasitemia till

28 days or until animals survived.

The in vitro antimalarial activity of the compounds was assessed

against CQ-sensitive 3D7 strain of P. falciparum and compared with

that of chloroquine. The schizontocidal activities (MIC) as well as

50% Inhibitory concentration (IC₅₀) were obtained following tech-

niques of Rickman’s et al. and Smilkstein et al., respectively.^7,8In

brief the parasites were maintained in vitro in RPNI medium (Sri-

vastava and Puri)⁹supplemented with gentamycin at 40

(Sigma), Fungizone at 0.25 g/mL; (GIBCO) and 10% foetal bovine

serum (pH 7.2), at 37 °C in a CO₂incubator.

lg/mL;

l

5.4. Docking studies

The compounds were dissolved in DMSO at 5 mg/mL and re-

quired dilutions were made in a template plate with RPMI med-

LigandFit, a modern docking program within Cerius2 version

4.10 (Cerius2 Version 4.10 (2005), Accelrys Inc., San Diego, USA),

was used for docking runs.¹²Reference protein coordinates for

docking were taken from the X-ray structure of Plasmodium falcipa-

rum TS-DHFR in complex with the pfDHFR inhibitor WR99210. The

site search was performed in the shape-based mode based on the

crystal structure of the compound WR99210. All calculations were

performed with the CFF 1.01 force ﬁeld. Conformations were gen-

erated with Monte Carlo simulations (10,000 trials) and Flexible ﬁt

was selected. A grid resolution was set to 0.5 Å. Electrostatic en-

ergy was included in the calculation of the ligand internal energy.

In order to avoid identical conformations, root mean square devia-

tion threshold of 1.5 Å and a score threshold of 20 kcal/mol were

used while saving the ﬁnal conformations. The top 10 conforma-

tions were saved after rigid body minimizations of 1000 steps.

Scoring was performed for each of the 10 saved ligand conforma-

tions using a set of scoring functions as implemented in Cerius2,

including LigScore1, LigScore2,¹³PLP1, PLP2,¹⁴JAIN,¹⁵PMF¹⁶and

LUDI.¹⁷Consensus scoring function was also used to evaluate and

rank the ligand binding afﬁnities.

ium. 20

lL from each dilution was transferred, in duplicate, in

the test plate and two wells receiving 20

l

L of vehicle were kept

as untreated control. For evaluation of schizontocidal activity par-

asite culture was synchronized using 5% D-sorbitol to obtain ring

stages only and 180 lL of 3% cell suspension containing 1% parasit-

ized cells was added to each well containing test compounds.¹⁰The

plates were incubated at 37 °C in CO₂incubator for more than 40 h.

after which thin smears were prepared from each well on grease-

free glass slides. These were ﬁxed in methanol, stained with Giem-

sa’s stain and examined under light microscope, 100x oil immer-

sion. The minimum inhibitory concentration (MIC) of test

compound was designated as the minimum concentration re-

quired producing 100% inhibition of schizont maturation.

Percent inhibition of maturation ¼ CS ꢂ TS ꢁ 100=CS

CS, No. of schizonts in untreated culture; TS, No. of schizonts in

treated culture.

For evaluation of IC₅₀of the compounds, SYBR Green I-based

ﬂuorescence (MSF) assay was used. For the assays, fresh dilutions

of all compounds in screening medium were prepared and 50 lL

of highest starting concentration (10–500 ng/mL) was dispensed

in duplicate wells in row ‘B’ of 96-well tissue culture plate. The

highest starting concentration for chloroquine was 25 ng/mL. Sub-

sequently twofold serial dilutions were prepared up to row ‘H’ (se-

5.5. In vitro antibacterial assay

The bacterial strains were grown on nutrient agar at 37 °C. After

24 h of incubation, bacterial cells were suspended in normal saline

containing Tween 20 at 0.05% at a concentration of approximately

1.0–2.0 ꢁ 10⁷cells/mL by matching with 0.5 McFarland standards.

The activity of compounds was determined by the NCCLS method

using Mueller Hinton broth (Sigma Chemical Co.). The 96-well tis-

sue culture plates were used with twofold serial dilution. Proper

growth control, drug control and the blank were adjusted onto

the plate. Compounds were dissolved in DMSO at a concentration

ven concentrations) and ﬁnally 50 lL of 2.5% parasitized cell

suspension containing 0.5% parasitemia was added to each well ex-

cept 4 wells in row ‘A’ received non infected cell suspension. These

wells containing non infected erythrocytes in the absence of com-

pound served as negative control, while parasitized erythrocytes in

the presence of CQ served as positive control. After incubating the

plates for 72 h, 100 lL of lysis buffer [20 mM Tris (pH 7.5), 5 mM

EDTA, 0.008% (wt/vol) saponin, and 0.08% (vol/vol) Triton X-100]

containing 1ꢁ concentration of SYBR Green-I was added to each

well and incubated for one hour at room temperature. The plates

were examined for the relative ﬂuorescence units (RFUs) per well

using the ﬂuorescence plate reader (FLUOstar, BMG labtechnolo-

gies). The IC₅₀was determined using Logit regression analysis of

dose-response curves.

of 1 mg/mL and 20

sue culture plate having 180

the solution was serially diluted resulting in twofold serial dilution

of the test compounds in subsequent wells. 100 L of Mc Farland

matched inoculum was diluted in 10 mL of meida and then inocu-

lum was added and kept for incubation. The drug was tested at a

maximum conc. of 50 mg/mL. Micro-titer plates were incubated

l

L of this was added to each well of 96-well tis-

lL Mueller Hinton broth. From here

l

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 203–221

221

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5. Monguchi, Y.; Kume, A.; Hattori, K.; Maegawa, T.; Sajiki, H. Tetrahedron 2006,

62, 7926.

at 35 °C in a moist, dark chamber and MICs were recorded spectro-

photometrically after 24 h incubation. For antibacterial screening,

compounds were tested against both gram negative and gram po-

sitive bacterial strains and Gentamicin was used as standard drug.

6. (a) Cunico, W.; Gomes, C. R. B.; Moreth, M.; Manhanini, D. P.; Figueiredo, I. H.;

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Kukreja, G.; Campiani, G.; Butini, S.; Bernetti, M.; Joshi, B. P.; Savini, L.; Basilico,

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Acknowledgments

Four authors (S.M., A.K., A.R., S.K.) acknowledge the ﬁnancial

support from CSIR, New Delhi in the form of fellowships. This work

was supported by the DST grant to Z.T. under WOS program.

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Search for new pharmacophores for antimalarial activity. Part I: Synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides

DOI: 10.1016/j.bmc.2008.11.021

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