Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas

Article abstract of DOI:10.1016/j.bmc.2008.11.009

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3-8 and 11-26, ureas 19-22, thioureas 23-26, and amides 27-54. Many of the CQ analogues prepared for this study showed submicromolar

Full text of DOI:10.1016/j.bmc.2008.11.009

Bioorganic & Medicinal Chemistry 17 (2009) 270–283
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl
amides, sulfonamides, ureas and thioureas
Kekeli Ekoue-Kovi a, Kimberly Yearick a, Daniel P. Iwaniuk a, Jayakumar K. Natarajan a,b, John Alumasa a,
a,c,
Angel C. de Dios a,c, Paul D. Roepe a,b,c, , Christian Wolf
*
*
a Department of Chemistry, Georgetown University, 37th and ‘‘O” Streets, Washington, DC 20057, USA
b Department of Biochemistry and Cellular and Molecular Biology, Georgetown University, 37th and ‘‘O” Streets, Washington, DC 20057, USA
c Center for Infectious Diseases, Georgetown University, 37th and ‘‘O” Streets, Washington, DC 20057, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-
derived sulfonamides 3–8 and 11–26, ureas 19–22, thioureas 23–26, and amides 27–54. Many of the
CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloro-
quine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance
indices were obtained in most cases. Systematic variation of the side chain length and introduction of
fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In par-
ticular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high anti-
plasmodial potency with a low resistance index and showed IC50s of 17.5 and 22.7 nM against HB3
and Dd2 parasites.
Received 19 September 2008
Revised 31 October 2008
Accepted 1 November 2008
Available online 12 November 2008
Keywords:
Chloroquine
4-Aminoquinolines
Sulfonamides
Ureas
Ó 2008 Elsevier Ltd. All rights reserved.
Thioureas
Amides
Malaria
1. Introduction
toporphyrin IX (FPIX) which is toxic to the parasite and generated
during proteolysis of host hemoglobin in the acidic food vacuole
Malaria is one of the world’s most widespread infectious diseases
afflicting approximately 300 million people annually. About 2
million people, mostly young children in tropical and subtropical
regions, die of malaria every year which corresponds to more than
5000 casualties per day. Malaria in humans is caused by protozoan
parasites of the genus Plasmodium and is transmitted by the Anoph-
eles mosquito. Although effective antimalarial agents have been
known for a long time, the alarming spread of drug resistant strains
of Plasmodium falciparum, which is the most lethal parasite species,
underscores the urgency and continuous need for the discovery of
new therapeutics. 7-Chloro-4-aminoquinoline derivatives including
chloroquine (CQ), sontoquine, and amodiaquine are among the most
potent antimalarial drugs reported to date,1–3 and new agents with
improved activity against CQ resistant (CQR) strains have been
introduced via synthetic modifications of the CQ side chain.4–7
Chloroquine and other aminoquinolines are commonly believed
to inhibit the formation of crystalline hemozoin from free ferripro-
in the infected red blood cell.8 The interaction between the
aminoquinoline ring of CQ and FPIX thus interferes with the
detoxification mechanism of the parasite and ultimately impedes
proliferation.9–15 The mechanism of CQ resistance is not fully
understood but it is known that resistant strains accumulate
reduced amounts of CQ in the digestive food vacuole (DV) relative
to their CQ sensitive (CQS) counterparts. This has been attributed
to mutations in the DV membrane protein Pfcrt (P. falciparum chlo-
roquine resistance transporter) which might result in reduced
accumulation of CQ in CQR strains.16–18 Since the trapping of high
concentrations of heme-targeted antimalarial drugs in the DV is
essential, many efforts have been directed to overcome the resis-
tance mechanism and the drug recognition by Pfcrt via modifica-
tion of the CQ side chain. Noteworthy, CQR reversal agents19,20
and new treatments21 such as artemisinin and related 1,2,4-triox-
olanes have been developed.22–27 A remaining drawback of 1,2,4-
trioxolanes is that they are generally less affordable in third world
countries while resistance to some organoperoxides has already
emerged.9,28,29 By contrast, 4-aminoquinolines are typically less
expensive and have good activity-toxicity profiles.30 The search
for new CQ analogues that are equally effective against CQS and
CQR strains has therefore received increasing attention during
* Corresponding authors. Tel.: +1 202 687 3468; fax: +1 202 687 6209 (C.W.); tel.:
+1 202 687 7300 (P.D.R.).
E-mail addresses: roepep@georgetown.edu (P.D. Roepe), cw27@georgetown.edu
(C. Wolf).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.11.009

K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
271
recent years. Various studies have revealed that structural changes
of the 7-chloroquinoline ring in CQ reduces the antimalarial activ-
ity,14,31 whereas modifications of the CQ side chain appears to be
more promising. We have prepared several 4-amino-7-chloroquin-
olyl-derived amides, sulfonamides, ureas and thioureas and discuss
the antimalarial activity of these new compounds herein, Figure 1.
methylene units between the 4-aminoquinoline moiety and the
tertiary amino function. Krogstad previously reported a somewhat
similar trend for the antimalarial potency of CQ derivatives with
varying side chain length against Indochina I, a CQR strain, but
not against Haiti 135, a CQS strain.40 Interestingly, comparison of
compounds 5 and 6 show that introduction of a methyl group,
which perfectly mimics the side chain of CQ, reduces the activity
against both strains tested. Exchange of the 6-dimethylamino-
naphthyl group in 3 by other aromatic groups furnished sulfona-
mides 11–14. These compounds gave similar RI values, ranging
from 1.4 to 4.1, but showed lower antimalarial activity than 3,
which indicates the significance of the terminal dansyl group.
The basic tertiary amino function in the side chain is commonly
believed to be crucial for the accumulation of the drug within
the acidic food DV. The IC50s of sulfonamides 15–18 therefore
increased into the micromolar range.
4-Amino-7-chloroquinolyl-derived ureas and thioureas 19–26
were prepared in good to high yields from N-(7-chloro-4-quino-
lyl)-1,3-diamine and the corresponding isocyanate and isothiocya-
nate, respectively, as shown in Scheme 2. Almost all compounds
studied showed submicromolar antiplasmodial activity (Table 1).
These results compare favorably with the majority of previously
reported chloroquine-derived ureas and thioureas.41,42 However,
Chibale et al. found that urea analogues of ferrochloroquine afford
superior antiplasmodial activity against a sensitive (D10) and a
resistant (K1) strain compared to CQ.43 In analogy to the sulfona-
mides discussed above, the low RI values of 19–26 are impressive
and suggest that incorporation of a rigid urea or thiourea group
into the side chain provides new leads that overcome drug resis-
tance to heme-targeted antimalarials.
The incorporation of amide functionalities into the side chain of
primaquine,44 amodiaquine45,46 and chloroquine47–51 has led to a
remarkable range of promising antimalarial agents. For compari-
son with the sulfonamides and ureas discussed above, we prepared
chloroquine-derived amides 27–45, Scheme 3. Coupling of
N-(7-chloro-4-quinolyl)-1,n-diaminoalkanes of varying chain
length and N,N-diethylamino-3-propionic acid in the presence of
1-[3-(dimethylaminopropyl]-3-ethylcarbodiimide (EDC) gave 27–
31. By contrast, we found that superior results in the syntheses
of 32–44 are obtained when 2-chloro-4,6-dimethoxy-1,3,5-triazine
(CDMT) is used as coupling agent. The anthranilic acids and
2-alkylthio- and 2-arylthiobenzoic acids used in the final coupling
step towards 32–36 were prepared as reported previously.52–54
Chloroquine-derived amide 45 was directly prepared from
N-(7-chloro-4-quinolyl)-1,3-diamine and 5-aminoisatoic anhy-
dride in 64% yield.
2. Results and discussion
Sulfonamides including the protease inhibitor and antiretroviral
fosamprenavir, the nonsteroidal anti-inflammatory drug celecoxib,
and sumatriptan, which has been used to treat migraine head-
aches, have found widespread use as pharmaceuticals. Among
the few examples of antimalarial sulfonamides reported to date,
some exhibit remarkable potency.32–35 We therefore decided to
prepare CQ-derived sulfonamides 3–8 and 11–18, Scheme 1.
Following a literature procedure, we synthesized 1 in 89% yield
from dansyl chloride and aminoethanol.36 Treatment of 1 with
methanesulfonyl chloride gave the corresponding mesylate 2 in
90% yield which allowed formation of sulfonamides 3–8 from a
series of N-(7-chloro-4-quinolyl)-1,n-diaminoalkanes. Reductive
amination of N-(7-chloro-4-quinolyl)-N0-ethyl-1,2-diaminoethane
in the presence of N-t-Boc-glycinal gave chloroquinoline 9 in 54%
yield. Deprotection furnished 10 which was then converted to
arylsulfonamides 11–14 in good yields. Using a similar approach,
15–18 were prepared from N-(7-chloro-4-quinolyl)-N0-propyl-
1,3-diaminoethane and an arylsulfonyl chloride in a single step.
The antiplasmodial activity of these compounds was measured
versus a CQS (HB3) and a CQR (Dd2) strain using a standardized,
inexpensive assay based on SYBR Green I intercalation.37–39 The
IC50 values were calculated from experiments carried out in tripli-
cate and compared to CQ (Table 1). Sulfonamides 3–8 represent a
series of CQ analogues with systematically varied side chain length
and a dansyl unit attached to the diethylamino terminus. All com-
pounds within this series showed antimalarial activity against both
strains tested and a low resistance index (RI). The RI provides a
quantitative measurement of the antiplasmodial activity against
CQR strains relative to that against CQS strains and reveals prom-
ising drug discovery leads. We found that the RI for 3–8 range from
0.5 to 3.6 whereas the resistance index of CQ was determined as
11.8. Most remarkable in this series is that the short chain 7-
chloro-4-aminoquinolyl sulfonamide 3 proved significantly more
potent against the resistant strain Dd2 relative to CQ. Compound
3 gave IC50s of 17.5 and 22.7 nM against HB3 and Dd2, respectively.
It thus retained its potency even when tested against a CQR strain.
An increase in the chain length proved detrimental to the antima-
larial activity. However, a maximum of the IC50s against the CQS
and the CQR strains was obtained for compound 4 exhibiting three
The amide series 27–31 shows high activity against HB3 (IC50
s
range from 16.3 to 31.5) but generally less potency against the chlo-
O
O
H
N
NEt2
N
HN
N
HN
N
N
H
R, Ar
Cl
HN
N
N
H
R, Ar
n
O
n=1-5
N
Cl
Cl
X
O
Ar
Ar
R
O
S
HN
N
H
N
H
HN
N
O
N
n
S
O
H
Ar
HN
N
N
N
S
O
H
HN
N
N
X=O,S
O
H
Cl
N
Cl
N
Cl
Cl
Fig. 1. General structures of tested 4-amino-7-chloroquinolyl-derived amides, sulfonamides, ureas and thioureas.

272
K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
N
N
N
Et3N
MsCl
Et3N
OH
+
H2N
O
S
O
O
S
O
HN
HN
O
S
Cl
O
1
2
, 89%
, 90%
OH
OMs
N
R
R
O
N
N
n
S
NH
n
HN
N
N
H
HN
N
O
DMF
+
3, R = H, n = 1, 79%
4, R = H, n = 2, 57%
O
HN
S
O
Cl
Cl
5
, R = H, n = 3, 75%
6, R = CH3, n = 3, 60%
R = H, n = 1-5
7
, R = H, n = 4, 75%
, R = H, n = 5, 76%
R = CH3, n = 3
OMs
2
8
NH
N
N
O
HN
N
HN
NHBoc
HCl
HN
NH2
BocHN
H
NaBH(OAc)3
N
Cl
Cl
N
9
Cl
N
, 54%
10, 88%
O
O
Ar
Ar =
S
HN
N
N
O
N
N
O
N
ArSO2Cl
Et3N
H
12, 53%
N
13, 67%
14
, 68%
11
, 61%
Cl
N
O
Ar =
Ar
O
S
N
HN
N
NH2
HN
N
H
ArSO2Cl
Et3N
15, 20%
16, 40%
Cl
N
Cl
O
O
N
N
17, 13%
18, 10%
Scheme 1. Synthesis of sulfonamides 3–8, 11–14 and 15–18.
roquine resistant strain Dd2 (Table 2). The IC50s against HB3 do not
vary substantially with the chain length. However, comparison of
the IC50s obtained with Dd2 reveals a maximum for 29 which has
four methylene groups between the 4-aminoquinolyl unit and the
amido nitrogen. Apparently, alteration of the chain length again
provides an effective tool in the search of new drug candidates that
retain their antiplasmodial potency against CQR strains. All other
amides prepared proved less effective against both HB3 and Dd2
but we noticed that the 2-benzylamino-4-fluorobenzoyl derivative
33 was significantly more active against Dd2 than HB3. The higher
activity against the CQR strain was even more surprising because
this was not the case for its defluorinated analogue 34.
Based on the relatively high activity of 33 against Dd2, we
decided to synthesize several additional fluorinated CQ amides
(Scheme 4). While amide 46 was prepared via CDMT mediated
coupling of 10 with the corresponding benzoic acid derivative, all
other amides were obtained using acyl chlorides. We were pleased
to find that these fluorinated CQ amides show improved activity
compared to 32–45 (Table 3). More importantly, fluoro amides
46–54 have excellent RI values ranging from 1.2 to 3.1. This com-
pares favorably with the high RIs determined for amides 27–31,
and it underscores that incorporation of fluorinated terminal
groups into the CQ side chain can possibly provide a means to cir-
cumvent the CQR mechanism.
3. Conclusion
More than 50 antiplasmodial 7-chloro-4-aminoquinolyl-de-
rived sulfonamides, ureas, thioureas and amides have been synthe-
sized and tested against CQR and CQS P. falciparum. Many of the CQ
analogues prepared for this study showed submicromolar antima-
larial activity versus HB3 and Dd2 and low resistance indices. The
effects of side chain length, the presence of urea, thiourea, amide
and sulfonamide functionalites, and the introduction of fluorinated
aliphatic and aromatic termini on the potency against CQS and CQR
strains of P. falciparum was investigated. Although none of the qui-
nolyl antimalarials tested was as active as CQ against HB3, more
importantly, sulfonamide 3 showed improved activity against the

K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
273
Table 1
diluted using complete media under sterile conditions and plated
in a 96-well plate format. Sorbitol synchronized cultures were
utilized with >95% of the parasites at the ring stage. Cultures were
diluted to give a working stock of 0.5% parasitemia and 2% hemat-
ocrit (final hematocrit 1% and 0.5% Parasitemia). The plates were
Antiplasmodial activity of CQ-derived sulfonamides, ureas and thioureas against HB3
and Dd2
a
Compound
Strain/IC50 (nM)
Dd2
HB3
10
18
115
82
RIb
incubated for 72 h at 37 °C. After 72 h, 50
l
L of 10ꢀ SYBR green I
CQ
3
4
5
6
127
23
411
125
260
12.7
1.3
3.6
1.5
1.2
1.7
0.5
2.0
4.1
1.4
1.7
1.3
1.3
—
—
1.9
—
1.6
1.5
1.5
3.9
1.8
2.1
dye was added to each well, and the plate was incubated for 1 h
at 37 °C. Fluorescence was measured at 530 nm (490 nm excita-
tion) using a spectra geminiEM plate reader. Data analysis was per-
formed using Sigma plot 9.0 software after downloading data in
Excel format. For each assay, each drug dilution was analyzed in
triplicate, and the results from at least two separate assays were
averaged in each case (SD < 10% in each case). All drugs were tested
against one chloroquine sensitive, and one chloroquine resistant
strain of P. falciparum (HB3 and Dd2, respectively). Based on
NMR spectroscopic and HPLC chromatographic analyses, all com-
pounds were at least of 98% purity.
220
70
7
8
115
147
274
512
443
286
966
607
>1000
>1000
596
>1000
674
539
353
801
272
140
124
310
171
754
453
>1000
960
316
281
436
365
229
208
272
291
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4.2. Synthesis
4.2.1. General
All reagents and solvents were commercially available and
used without further purification. Flash chromatography was per-
formed on Kieselgel 60, particle size 0.032–0.063 mm. NMR spec-
482
606
tra were obtained on a 300 MHz (1H NMR) and 75 MHz (13
C
a
IC50 values were obtained from an average of two separate determinations each
performed in triplicate.
NMR) Varian FT-NMR spectrometer using CDCl3 as solvent unless
indicated otherwise. N-(7-Chloro-4-quinolyl)-1,n-diaminoalkanes
and N-(7-chloro-4-quinolyl)-N0-ethyl-1,n-diaminoalkane deriva-
tives were synthesized following a procedure reported in the
literature.55
b
Resistance index (CQR-IC50/CQS-IC50).
CQR strain Dd2. The results revealed interesting SAR principles
leading to promising new directions for the design of antimalarials
that address CQ resistance. In particular, sulfonamide 3 exhibiting
a short side chain with a terminal dansyl moiety proved signifi-
cantly more potent against the resistant strain Dd2 than CQ, and
incorporation of fluorinated termini into the CQ side chain gave
desirable RI indices.
4.2.1.1. 2-(5-Dimethylaminonaphthalene-1-sulfonamido)ethyl
methanesulfonate, 2. To a solution of 5-dimethylamino-N-(2-
hydroxyethyl)naphthalene-1-sulfonamide, 1 (1.5 g, 5.1 mmol) and
Et3N (1.07 mL, 7.64 mmol) in anhydrous CH2Cl2, methanesulfonyl
chloride (0.44 mL, 5.61 mmol) was added at room temperature
and stirred for 1 h. After addition of water, the reaction mixture
was extracted with CH2Cl2, dried over anhydrous Na2SO4 and con-
centrated in vacuo. Flash chromatography using EtOAc:hexanes
(1:4 v/v) as mobile phase and gradually changing the ratio of
EtOAc:hexanes to 1:1.7 (v/v) afforded 1.71 g (4.6 mmol, 90% yield)
of a light yellow oil. 1H NMR (300 MHz, CDCl3) d = 2.86 (s, 3H), 2.89
(s, 6H), 3.27 (m, 2H), 4.17 (t, J = 6.0 Hz, 2H), 5.11 (t, J = 6.0 Hz, 1H),
7.21 (d, J = 7.5 Hz, 1H), 7.50–7.64 (m, 2H), 8.22–8.28 (m, 2H), 8.57
4. Experimental
4.1. Cell culture and antimalarial activity measurements
Drug activities were assessed and IC50 were quantified essen-
tially as described previously.37–39 The aminoquinolines were
X
R
HN
NH2
HN
N
N
H
N
H
ArNCX
Cl
H3CO
H3CO
N
Cl
Ar =
23
19
OCH3
, X = S, 51%
OCH3
, X = O, 89%
Ar =
NO2 20, X = O, 83%
NO2 24, X = S, 76%
H3CO
21
, X = O, 84%
NMe2 25, X = S, 67%
NMe2 26, X = S, 96%
NMe2
22
, X = O, 82%
Scheme 2. Preparation of ureas and thioureas 19–26.

274
K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
H
.
N
N
HCl
NH2
HN
HN
N
HO
N
27
n
, n = 1, 63%
n
O
28, n = 2, 54%
O
29
30
, n = 3, 60%
, n = 4, 12%
EDC
Cl
Cl
N
31, n = 5, 76%
n = 1-5
O
HN
NH2
+
HN
N
N
H
Ar
O
CDMT
Ar
OH
NMM
Cl
S
Cl
N
t
-BuO
O
NH
HN
HN
S
HN
NH
Ar =
F
32
33, 59%
34
, 68%
36
, 25%
37
38
, 73%
35, 35%
, Boc-D-Trp-OH, 60%
, Boc-Trp-OH, 40%
O
t
-BuO
H
N
O
t
-BuO
NH
O
N
N
N
N
H
O
N
, 20%
N
OH
39
, 30%
41
43, 25%
40
42, 25%
44
, 35%
, 55%
O
NH2
HN
N
NH2
O
HN
N
N
H
H2N
O
+
NH2
45, 64%
Cl
N
H
O
Cl
Scheme 3. Synthesis of amides 27–45.
4.2.1.2. Representative procedure for the synthesis of sulfon-
amide analogs 3–8. A solution of N-(7-chloro-4-quinolyl)-N’-
Table 2
Antiplasmodial activity of CQ-derived amides against HB3 and Dd2
a
ethyl-1,4-diaminobutane (0.076 g, 0.27 mmol) and
2 (0.05 g,
Compound
Strain/IC50 (nM)
Dd2
0.14 mmol) in anhydrous DMF was heated at 90° C for 3 h. After
cooling to room temperature, DMF was removed in vacuo. Satu-
rated NaHCO3 solution was added to the residue, which was then
extracted with CH2Cl2, dried over anhydrous Na2SO4 and concen-
trated in vacuo. Flash chromatography using MeOH:CH2Cl2 (1:19
v/v) as the mobile phase gave 0.056 g (0.1 mmol, 75% yield) of 5
as a yellow oil. For the syntheses of 3, 4 and 7, the reactions were
carried out in anhydrous THF and refluxed for 60 h.
HB3
10
RIb
CQ
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
127
760
559
>1000
672
385
>1000
305
>1000
>1000
>1000
764
>1000
>1000
>1000
>1000
>1000
792
12.7
24.1
24.4
—
41.2
12.9
—
—
—
—
—
1.5
—
—
—
—
—
1.8
—
32
23
29
16
28
>1000
>1000
>1000
>1000
>1000
500
479
902
>1000
>1000
>1000
449
4.2.1.3. N-[2-{(N0-4-(7-chloro-4-quinolyl)aminobutyl-N00-ethyl}-
aminoethyl]-5-dimethylaminonaphthalene-1-sulfonamide, 5.
1H NMR (300 MHz, CDCl3) d = 0.79 (t, J = 7.2 Hz, 3H), 1.44 (m,
2H), 1.64 (m, 2H), 2.22–2.34 (m, 4H), 2.43 (t, J = 6.0 Hz, 2H), 2.85
(s, 6H), 2.91 (t, J = 6.0 Hz, 2H), 3.24 (q, J = 6.0 Hz, 2H), 5.32 (bs,
1H), 6.37 (d, J = 5.4 Hz, 1H), 7.13 (dd, J = 0.9 Hz, J = 7.5 Hz, 1H),
7.32 (dd, J = 2.1 Hz, J = 8.7 Hz, 1H), 7.46–7.56 (m, 2H), 7.76 (d,
J = 9.3 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 8.25 (dd, J = 1.2 Hz,
J = 7.5 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.50–8.57 (m, 2H); 13C
NMR (75 MHz, CDCl3) d = 11.1, 24.6, 26.4, 40.4, 42.9, 45.3, 46.7,
51.5, 52.1, 98.8, 115.0, 117.1, 118.7, 121.5, 123.0, 125.1, 128.2,
129.5, 129.6, 129.7, 130.3, 134.3, 134.8, 148.7, 149.9, 151.6, 151.9.
756
179
>1000
651
3.6
a
IC50 values were obtained from an average of two separate determinations each
in triplicate.
b
Resistance index (CQR-IC50/CQS-IC50).
(d, J = 5.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) d = 37.0, 42.1, 45.2,
68.1, 115.2, 118.5, 123.1, 128.5, 129.2, 129.4, 129.7, 130.6, 134.3,
151.9.
4.2.1.4. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]-5-dimethylaminonaphthalene-1-sulfonamide, 3.
Employing 0.16 g (0.44 mmol) of 2, 0.15 g (0.6 mmol) of

K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
275
O
HN
N
N
HN
NH2
+
HN
N
N
H
HN
O
F
CDMT
NMM
HO
46,
66%
Cl
Cl
N
F
10
O
HN
N
NH2
HN
N
H
R
RCOCl
Et3N
Cl
Cl
N
F2
C
F2
F
F
F
F
F3C
F3C
C
R =
C
C
F2
F2
O
O
5
F3C
CF3
F
49, 49%
50, 25%
47, 59%
48, 65%
O
N
N
HN
NH2
HN
N
H
R
RCOCl
Et3N
Cl
N
Cl
N
10
F2
F2
F
F
F
F
F3C
C
F3C
C
R =
C
C
F2
F2
O
O
5
F3C
CF3
, 39%
F
53
54
, 16%
, 42%
51
52
, 23%
Scheme 4. Synthesis of amides 46–54.
Table 3
(d, J = 5.4 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.28–7.50 (m, 3H),
7.73 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 8.20 (dd,
J = 1.2 Hz, J = 7.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.45–8.56 (m,
2H); 13C NMR (75 MHz, CDCl3) d = 10.9, 39.9, 40.8, 45.1, 46.6,
50.8, 52.0, 98.7, 114.9, 117.0, 118.4, 121.6, 122.9, 125.0, 127.7,
128.1, 129.1, 129.3, 129.6, 130.2, 134.5, 134.6, 148.4, 149.6,
151.5, 151.7.
Antiplasmodial activity of fluorinated CQ-derived amides 46–54
a
Compound
Strain/IC50 (nM)
Dd2
HB3
RIb
CQ
46
47
48
49
50
51
52
53
54
10
80
127
199
236
510
277
197
137
314
556
87
12.7
2.5
1.6
1.9
1.2
1.2
1.4
2.7
3.1
1.2
145
276
234
166
97
118
180
72
4.2.1.5. N-[2-{(N0-3-(7-chloro-4-quinolyl)aminopropyl-N00-ethyl}-
aminoethyl]-5-dimethylaminonaphthalene-1-sulfonamide, 4.
Employing 0.16 g (0.44 mmol) of 2 , 0.15 g (0.6 mmol) of N-
(7-chloro-4-quinolyl)-N0-ethyl-1,3-diaminopropane and 0.3 mL
(1.7 mmol) of N,N-diisopropylethylamine in the procedure de-
scribed above and purification by flash chromatography using
MeOH:CH2Cl2 (1:19 v/v) as the mobile phase furnished 0.133 g
(0.25 mmol, 57% yield) of a yellow oil. 1H NMR (300 MHz, CDCl3)
d = 0.88 (t, J = 7.2 Hz, 3H), 1.74 (m, 2H), 2.35–2.49 (m, 4H), 2.52
(t, J = 6.0 Hz, 2H), 2.84 (s, 6H), 2.97 (t, J = 6.0 Hz, 2H), 3.24 (q,
J = 6.0 Hz, 2H), 5.48 (bs, 1H), 6.03 (bs, 1H), 6.30 (d, J = 5.4 Hz,
1H), 7.10 (d, J = 7.5 Hz, 1H), 7.28 (m, 1H), 7.40–7.52 (m, 2H),
7.61 (d, J = 8.7 Hz, 1H), 7.93 (t, J = 1.8 Hz, 1H), 8.21 (dd,
J = 1.2 Hz, J = 7.5 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.47–8.55 (m,
2H); 13C NMR (75 MHz, CDCl3) d = 11.0, 25.1, 40.6, 42.2, 45.2,
47.1, 51.5, 52.2, 98.5, 115.0, 177.1, 118.5, 121.6, 122.9, 124.9,
128.0, 128.2, 129.3, 129.4, 129.6, 130.3, 134.3, 134.5, 148.7,
150.0, 151.6, 151.8.
a
IC50 values are an average of two separate determinations each done in
triplicate.
b
Resistance index (IC50 CQR)/(IC50 CQS).
N-(7-chloro-4-quinolyl)-N0-ethyl-1,2-diaminoethane and 0.3 mL
(1.7 mmol) of N,N-diisopropylethylamine in the procedure de-
scribed above and purification by flash chromatography using
MeOH:CH2Cl2 (1:19 v/v) as the mobile phase gave 0.18 g (0.33
mmol, 79% yield) of a yellow oil. 1H NMR (300 MHz, CDCl3)
d = 0.87 (t, J = 7.2 Hz, 3H), 2.42 (q, J = 7.2 Hz, 2H), 2.55
(t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz, 2H), 2.84 (s, 6H), 2.99
(t, J = 5.7 Hz, 2H), 3.19 (q, J = 5.7 Hz, 2H), 5.61 (bs, 2H), 6.25

276
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4.2.1.6. N-[2-{(N0-4-(7-chloro-4-quinolyl)aminopentyl-N00-ethyl}-
aminoethyl]-5-dimethylaminonaphthalene-1-sulfonamide, 6.
Employing 0.063 g (0.17 mmol) of 2 and 0.1 g (0.34 mmol) of
monodesethylchloroquine56 in the procedure described above
and purification by flash chromatography using MeOH:CH2Cl2
(1:19 v/v) as the mobile phase afforded 0.058 g (0.10 mmol, 60%
yield) of a yellow oil. 1H NMR (300 MHz, CDCl3) d = 0.76 (t,
J = 7.2 Hz, 3H), 1.31 (d, J = 6.3 Hz, 3H), 1.36–1.72 (m, 4H), 2.16–
2.33 (m, 4H), 2.40 (m, 2H), 2.81–2.96 (m, 8H), 3.66 (m, 1H), 4.96
(d, J = 7.8 Hz, 1H), 5.51 (bs, 1H), 6.38 (d, J = 5.4 Hz, 1H), 7.13 (d,
J = 7.5 Hz, 1H), 7.34 (m, 1H), 7.46–7.57 (m, 2H), 7.74 (d,
J = 9.3 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 8.25 (m, 1H), 8.31 (d,
J = 9.0 Hz, 1H), 8.48–8.58 (m, 2H); 13C NMR (75 MHz, CDCl3)
d = 11.2, 20.2, 23.6, 34.3, 40.3, 45.3, 46.6, 48.2, 51.5, 52.5, 99.0,
115.0, 117.1, 118.7, 121.3, 123.0, 125.0, 128.2, 128.4, 129.5,
129.6, 129.8, 130.5, 134.3, 134.7, 149.0, 149.1, 151.7, 151.9.
(dd, J = 2.4 Hz, J = 9.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.92 (d,
J = 2.4 Hz, 1H), 8.47 (d, J = 5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d = 11.6, 28.1, 38.5, 39.8, 47.2, 51.2, 52.6, 78.9, 98.9, 117.1, 121.3,
125.0, 128.0, 134.5, 148.6, 149.7, 151.6, 155.9.
4.2.1.10. N-Ethyl-N-[2-(7-chloro-4-quinolyl)aminoethyl]-1,2-
diaminoethane, 10. To a solution of 9 (0.25 g, 0.62 mmol) in anhy-
drous methanol, 2 M HCl (3.1 mL, 6.2 mmol) was added at room
temperature and stirred overnight. The solvents were removed in
vacuo. The reaction mixture was basified with 10 N NaOH, ex-
tracted with dichloromethane, dried over anhydrous Na2SO4 and
concentrated in vacuo to 0.17 g (0.57 mmol, 88% yield) of a brown
oil. 1H NMR (300 MHz, CD3OD) d = 1.43 (t, J = 7.2 Hz, 3H), 3.40–3.58
(m, 4H), 3.60–3.78 (m, 4H), 4.16 (m, 2H), 7.13 (d, J = 6.9 Hz, 1H),
7.73 (dd, J = 1.8 Hz, J = 9.0 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 8.53 (d,
J = 6.9 Hz, 1H), 8.64 (d, J = 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d = 11.5, 39.6, 40.1, 47.2, 50.9, 55.5, 98.8, 117.2, 121.5, 124.7,
128.1, 134.3, 148.8, 149.8, 151.7.
4.2.1.7. N-[2-{(N0-5-(7-chloro-4-quinolyl)aminopentyl-N00-ethyl}-
aminoethyl]-5-dimethylaminonaphthalene-1-sulfonamide, 7.
Employing 0.064 g (0.17 mmol) of 2 and 0.1 g (0.34 mmol) of N-
(7-chloro-4-quinolyl)-N0-ethyl-1,5-diaminopentane in the proce-
dure described above and purification by flash chromatography
using MeOH:CH2Cl2 (1:19 v/v) as the mobile phase afforded
0.073 g (0.13 mmol, 75% yield) of a yellow oil. 1H NMR (300 MHz,
CDCl3) d = 0.76 (t, J = 7.2 Hz, 3H), 1.29–1.39 (m, 4H), 1.67 (m, 2H),
2.16–2.28 (m, 4H), 2.39 (t, J = 6.0 Hz, 2H), 2.82–2.93 (m, 8H), 3.28
(q, J = 6.0 Hz, 2H), 5.36 (t, J = 4.8 Hz, 1H), 6.37 (d, J = 5.7 Hz, 1H),
7.14 (d, J = 7.2 Hz, 1H), 7.26 (dd, J = 2.4 Hz, J = 9.0 Hz, 1H), 7.47–
7.57 (m, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 8.25
(dd, J = 1.5 Hz, J = 7.2 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.48–8.58
(m, 2H); 13C NMR (75 MHz, CDCl3) d = 11.1, 24.9, 26.6, 28.4, 40.3,
43.1, 45.3, 46.6, 51.4, 52.3, 98.8, 115.0, 117.1, 118.7, 121.5, 123.0,
125.0, 128.1, 128.2, 129.5, 129.5, 129.7, 130.2, 134.2, 134.7,
148.8, 149.9, 151.6, 151.8.
4.2.1.11. Representative procedure for the synthesis of sulfon-
amide analogs 11–14. To a solution of N-(7-chloro-4-quinolyl)-N0-
ethyl-N0-(2-aminoethyl)-1,2-diaminoethane 10 (0.055 g, 0.21
mmol) and Et3N (0.06 mL, 0.42 mmol) in anhydrous CH2Cl2,
6-phenoxypyridine–3-sulfonyl chloride (0.06 g, 0.21 mmol) was
added and the mixture was stirred at room temperature for 1 h.
Saturated NaHCO3 solution was added to the reaction mixture,
which was then extracted with CH2Cl2, dried over anhydrous
Na2SO4, and concentrated in vacuo. Flash chromatography using
MeOH:CH2Cl2 (1:49 v/v) and gradually changing the ratio of
MeOH:CH2Cl2 to 1:19 (v/v) gave 0.065 g (0.12 mmol, 61% yield)
of a yellow oil.
4.2.1.12. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]-2-phenoxy-5-pyridinesulfonamide, 11. 1H NMR
(300 MHz, CDCl3) d = 1.00 (t, J = 7.2 Hz, 3H), 2.60 (q, J = 7.2 Hz,
2H), 2.69 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H), 3.10 (t,
J = 6.0 Hz, 2H), 3.18 (q, J = 6.0 Hz, 2H), 5.92 (bt, 1H), 6.09 (d,
J = 5.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 7.09–7.16 (m, 1H), 7.21–
7.30 (m, 2H), 7.37–7.46 (m, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.74 (d,
J = 2.1 Hz, 1H), 8.02 (dd, J = 2.7 Hz, J = 8.7 Hz, 1H), 8.34 (d,
J = 5.4 Hz, 1H), 8.63 (d, J = 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d = 11.1, 39.8, 40.9, 46.8, 50.9, 52.0, 98.6, 111.3, 116.8, 121.3,
121.7, 125.3, 125.5, 127.3, 129.7, 131.1, 134.8, 138.1, 147.3,
147.9, 149.6, 151.3, 152.8, 165.8.
4.2.1.8. N-[2-{(N0-6-(7-chloro-4-quinolyl)aminohexyl-N00-ethyl}-
aminoethyl]-5-dimethylaminonaphthalene-1-sulfonamide, 8.
Employing 0.091 g (0.25 mmol) of 2 and 0.15 g (0.49 mmol) of N-
(7-chloro-4-quinolyl)-N0-ethyl-1,6-diaminohexane in the proce-
dure described above and purification by flash chromatography
using MeOH:CH2Cl2 (1:19 v/v) as the mobile phase provided
0.108
g (0.19 mmol, 76% yield) of a
yellow oil. 1H NMR
(300 MHz, CDCl3) d = 0.74 (t, J = 7.2 Hz, 3H), 1.20-1.50 (m, 6H),
1.76 (m, 2H), 2.14–2.28 (m, 4H), 2.39 (t, J = 6.0 Hz, 2H), 2.81–2.94
(m, 8H), 3.31 (q, J = 7.2 Hz, 2H), 5.24 (bs, 1H), 6.40 (d, J = 5.4 Hz,
1H), 7.14 (d, J = 7.5 Hz, 1H), 7.28 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H),
7.48–7.58 (m, 2H), 7.74 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H),
8.25 (dd, J = 1.2 Hz, J = 7.2 Hz, 1H), 8.32 (d, J = 8.7 Hz, 1H), 8.49–
8.58 (m, 2H); 13C NMR (75 MHz, CDCl3) d = 11.1, 26.6, 26.8, 26.9,
28.5, 40.3, 43.0, 45.2, 46.5, 51.4, 52.3, 98.7, 115.0, 117.1, 118.6,
121.5, 123.0, 124.9, 128.1, 129.5, 129.7, 130.2, 134.2, 134.6,
148.7, 150.0, 151.6, 151.8.
4.2.1.13. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]-3-pyridinesulfonamide, 12. Employing 0.045 g
(0.26 mmol) of 3-pyridinesulfonyl chloride and 0.075 g (0.26
mmol) of 10 in the procedure described above followed by flash
chromatography using MeOH:CH2Cl2 (1:19 v/v) and gradually
changing the ratio of MeOH:CH2Cl2 to 1:9 (v/v) afforded 0.06 g
(0.13 mmol, 53% yield) of a yellow oil. 1H NMR (300 MHz, CDCl3)
d = 1.02 (t, J = 7.2 Hz, 3H), 2.61 (q, J = 7.2 Hz, 2H), 2.70 (t,
J = 6.0 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 3.13 (t, J = 6.0 Hz, 2H), 3.19
(q, J = 6.0 Hz, 2H), 5.86 (bt, 1H), 6.11 (d, J = 5.4 Hz, 1H), 7.28 (dd,
J = 2.1 Hz, J = 9.0 Hz, 1H), 7.35 (m, 1H), 7.64 (d, J = 9.0 Hz, 1H),
7.75 (d, J = 2.1 Hz, 1H), 8.05 (m, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.74
(dd, J = 1.8 Hz, J = 5.1 Hz, 1H), 9.06 (dd, J = 0.9 Hz, J = 2.4 Hz, 1H);
13C NMR (75 MHz, CDCl3) d = 11.1, 39.8, 40.9, 46.9, 50.9, 52.0,
98.8, 116.9, 121.6, 123.6, 125.3, 127.5, 134.4, 134.8, 136.8, 147.7,
148.1, 149.5, 151.5, 152.9.
4.2.1.9. N-t-Boc N0-ethyl-N0-[2-(7-chloro-4-quinolyl)aminoethyl]-
1,2-diaminoethane, 9. To a solution of N-(7-chloro-4-quinolyl)-N0-
ethyl-1,2-diaminoethane (0.95 g, 3.8 mmol) and N-t-Boc-glycinal57
(1.1 g, 6.9 mmol) in anhydrous CH2Cl2, sodium triacetoxyborohy-
dride (1.46 g, 6.9 mmol) was added at room temperature and stirred
for 24 h. The reaction mixture was quenched with water, basified
with 10 N NaOH and extracted with dichloromethane. The com-
bined organic layers were dried over anhydrous Na2SO4 and concen-
trated in vacuo. Flash chromatography using MeOH:CH2Cl2 (1:24 v/
v) as the mobile phase afforded 0.8 g (2.0 mmol, 54% yield) of a
yellow oil. 1H NMR (300 MHz, CDCl3) d = 1.05 (t, J = 7.2 Hz, 3H),
1.34 (s, 9H), 2.56–2.70 (m, 4H), 2.81 (t, J = 6.0 Hz, 2H), 3.15–3.36
(m, 4H), 5.25 (bs, 1H), 6.08 (s, 1H), 6.31 (d, J = 5.4 Hz, 1H), 7.30
4.2.1.14. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]-8-quinolinesulfonamide, 13. Employing 0.04 g
(0.17 mmol) of quinoline-8-sulfonyl chloride and 0.05 g (0.17
mmol) of 10 in the procedure described above followed by flash

K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
277
chromatography using MeOH:CH2Cl2 (1:49 v/v) and gradually
changing the ratio of MeOH:CH2Cl2 to 1:24 (v/v) generated
0.056 g (0.12 mmol, 67% yield) of yellow crystals. 1H NMR
(300 MHz, CDCl3) d = 0.88 (t, J = 7.2 Hz, 3H), 2.42 (q, J = 7.2 Hz,
2H), 2.62 (t, J = 6.0 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.98 (q,
J = 6.0 Hz, 2H), 3.22 (q, J = 6.0 Hz, 2H), 5.98 (t, J = 4.2 Hz, 1H), 6.28
(d, J = 5.4 Hz, 1H), 6.72 (t, J = 5.4 Hz, 1H), 7.29 (dd, J = 2.1 Hz,
J = 8.7 Hz, 1H), 7.41 (dd, J = 5.2 Hz, J = 8.1 Hz, 1H), 7.59 (dd,
J = 7.2 Hz, J = 8.1 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.90 (d,
J = 2.1 Hz, 1H), 7.99 (dd, J = 1.5 Hz, J = 8.1 Hz, 1H), 8.18 (dd,
J = 1.5 Hz, J = 8.1 Hz, 1H), 8.39 (dd, J = 1.5 Hz, J = 7.2 Hz, 1H), 8.48
(d, J = 5.4 Hz, 1H), 8.77 (dd, J = 1.5 Hz, J = 4.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d = 10.9, 39.9, 41.2, 46.3, 50.9, 52.1, 61.5, 98.8,
98.9117.1, 121.8, 122.0, 122.1, 125.4, 125.4, 125.5, 128.0, 128.5,
131.1, 133.3, 134.8, 135.2, 136.9, 142.9, 148.6, 149.7, 150.9,
151.5, 151.6.
J = 2.2 Hz, J = 9.0 Hz, 1H), 7.65–7.74 (m, 2H), 7.76 (d, J = 2.2 Hz,
1H), 8.12 (d, J = 9.1 Hz, 1H), 8.24 (dd, J = 1.3 Hz, J = 8.3 Hz,
1H), 8.30–8.34 (m, 2H), 8.49 (dd, J = 1.8 Hz, J = 8.4 Hz, 1H), 9.03
(dd, J = 1.8 Hz, J = 4.2 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
d = 27.6, 39.6, 40.7, 98.4, 117.2, 122.4, 124.0, 125.6, 127.1,
128.4, 130.6, 133.4, 133.5, 136.2, 136.9, 142.6, 148.6, 149.9,
151.2, 151.5.
4.2.1.19. N-(N0-3-(7-chloro-4-quinolyl)aminopropyl)-2-phenoxy-
5-pyridinesulfonamide, 17. Employing 0.15 g (0.64 mmol) of N-
(7-chloro-4-quinolyl)-1,3-diaminopropane and 6-phenoxy-3-pyr-
idinesulfonyl chloride (0.2 g, 0.76 mmol) in the procedure
described above gave 0.038 g (0.081 mmol, 13% yield) of white
crystals. 1H NMR (300 MHz, CDCl3) d = 1.94 (tt, J = 6.2 Hz,
J = 6.2 Hz, 2H), 3.16 (t, J = 6.2 Hz, 2H), 3.54 (dt, J = 6.2 Hz, 2H),
5.57 (bs, 1H), 6.32 (d, J = 5.7 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 7.13
(d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 2.0 Hz,
J = 8.9 Hz, 1H), 7.41–7.46 (m, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.90 (d,
J = 1.9 Hz, 1H), 8.08 (dd, J = 2.7 Hz, J = 8.6 Hz, 1 H), 8.46 (d,
J = 5.7 Hz, 1H), 8.64 (d, J = 2.7 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) d = 28.5, 41.2, 99.4, 112.4, 118.1, 122.3, 124.8, 126.1, 128.1,
130.6, 132.4, 134.1, 139.4, 147.1, 149.6, 150.7, 152.5, 153.6, 165.8.
4.2.1.15. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-
sulfonamide, 14. Employing 0.045 g (0.18 mmol) of 4-methyl-3,4-
dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride and 0.053 g
(0.18 mmol) of 10 in the procedure described above followed by
flash chromatography using MeOH:CH2Cl2 (1:16 v/v) as the mobile
phase afforded 0.062 g (0.12 mmol, 68% yield) of a yellow oil. 1H
NMR (300 MHz, CDCl3) d = 0.97 (t, J = 7.2 Hz, 3H), 2.54 (q,
J = 7.2 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.72–2.81 (m, 5H), 3.04 (t,
J = 6.0 Hz, 2H), 3.16–3.30 (m, 4H), 4.27 (t, J = 4.5 Hz, 2H), 5.80 (bs,
1H), 5.91 (bt, 1H), 6.22 (d, J = 5.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H),
7.06 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 2.1 Hz, J = 8.4 Hz, 1H), 7.33
(dd, J = 2.1 Hz, J = 9.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.86 (d,
J = 2.1 Hz, 1H), 8.44 (d, J = 5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d = 11.2, 38.4, 40.1, 40.9, 46.9, 48.1, 51.0, 52.1, 64.8, 98.7, 110.3,
115.7, 117.0, 117.2, 121.8, 125.5, 127.6, 131.6, 135.0, 136.7,
147.5, 148.1, 149.8, 151.2.
4.2.1.20. N-(N0-3-(7-chloro-4-quinolyl)aminopropyl)-4-methyl-
3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide, 18. Employ-
ing 0.102 g (0.43 mmol) of N-(7-chloro-4-quinolyl)-1,3-diaminopro-
pane and 1,4-benzoxazinesulfonyl chloride (0.123 g, 0.49 mmol) in
the procedure described above provided 0.02 g (0.04 mmol, 10% yield)
of off-white crystals. 1H NMR (400 MHz, CDCl3) d = 1.79-1.86 (m, 2H),
2.76 (s, 3H), 3.02 (t, J = 4.5 Hz, 2H), 3.19 (t, J = 3.4 Hz, 2H), 3.44 (t,
J = 4.5 Hz, 2H), 4.23 (t, J = 3.8 Hz, 2H), 5.79 (bs, 1H), 6.25 (d,
J = 4.1 Hz, 1H), 6.72 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 1.5 Hz, 1H), 7.06
(dd, J = 1.8 Hz, J = 6.6 Hz, 1H), 7.28 (dd, J = 1.8 Hz, J = 6.6 Hz, 1H),
7.72 (d, J = 6.6 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 8.37 (d, J = 4.1 Hz,
1H); 13C NMR (75 MHz, CDCl3) d = 26.8, 32.0, 37.5, 38.6, 39.5, 47.3,
63.9, 97.7, 109.3, 115.0, 116.3, 120.5, 124.5, 127.2, 134.2, 135.9,
146.8, 148.7, 150.4, 164.2.
4.2.1.16. Representative procedure for the synthesis of sulfon-
amide analogs 15–18. To a mixture of N-(7-chloro-4-quinolyl)-
1,3-diaminopropane (0.15 g, 0.64 mmol) in 4.5 mL of anhydrous
THF under nitrogen at room temperature was added triethylamine
(0.084 g, 0.83 mmol) and dansyl chloride (0.21 g, 0.76 mmol). After
stirring for 36 h at room temperature, the mixture was quenched
with water and extracted with dichloromethane. The combined or-
ganic layers were dried over anhydrous MgSO4, concentrated in va-
cuo, and purified by recrystallization from chloroform to give 15 as
a white solid (0.06 g, 0.13 mmol, 20% yield).
4.2.1.21. Representative procedure for the synthesis of urea
(19–22) and thiourea 23–26 analogs. A mixture of N-(7-chloro-4-
quinolyl)-1,3-diaminopropane (0.15 g, 0.64 mmol) and the appro-
priate isothiocyanate or isocyanate (0.53 mmol) in anhydrous
THF was stirred at room temperature until the reaction was com-
plete. In all cases, the desired urea or thiourea product precipitated
from solution. The precipitate was collected via vacuum filtration
and dried in vacuo.
4.2.1.17. N-(N0-3-(7-chloro-4-quinolyl)aminopropyl)-5-dimeth-
ylaminonaphthalene-1-sulfonamide, 15. 1H NMR (300 MHz,
DMSO-d6) d = 1.69 (tt, J = 6.6 Hz, J = 6.6 Hz, 2H), 2.80 (s, 6H), 2.94
(dt, J = 6.6 Hz, J = 6.1 Hz, 2H), 3.10 (dt, J = 6.6 Hz, J = 5.8 Hz, 2H),
6.16 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 5.8 Hz, 1H), 7.23 (d, J = 7.9 Hz,
1H), 7.41 (dd, J = 2.2 Hz, J = 8.5 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H),
7.59 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.99 (t, J = 6.1 Hz,
1H), 8.09 (dd, J = 1.0 Hz, J = 7.3 Hz, 1H), 8.15 (d, J = 7.3 Hz, 1H),
8.30 (m, 2 H), 8.41 (d, J = 7.3 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) d = 27.8, 45.0, 98.4, 115.0, 117.3, 118.9, 123.43, 123.9, 127.3,
127.8, 128.3, 129.0, 129.3, 133.3, 135.8, 148.8, 149.80, 151.3, 151.6
4.2.1.22. N-(3-(7-chloro-4-quinolyl)aminopropyl)-N0-(4-methoxy-
phenyl)urea, 19. Employing 0.195 g (0.83 mmol) of N-(7-chloro-4-
quinolyl)-1,3-diaminopropane and 4-methoxyphenyl isocyanate
(0.09 mL, 0.69 mmol) in the procedure described above gave
0.244 g (0.64 mmol, 89
%
yield) of white crystals. 1H NMR
(300 MHz, DMSO-d6) d = 1.81–1.89 (m, 2H), 3.19–3.38 (m, 4H),
3.73 (s, 3H), 6.18 (t, J = 5.6 Hz, 1H), 6.52 (d, J = 5.6 Hz, 2H), 6.85
(dd, J = 2.1 Hz, J = 6.7 Hz, 2H), 7.31–7.37 (m, 3H), 7.49 (dd,
J = 3.2 Hz, J = 10.0 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 8.30 (d,
J = 2.7 Hz , 1H), 8.32 (s, 1H), 8.44 (d, J = 5.4 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) d = 25.8, 29.3, 37.8, 55.8, 114.9, 118.2, 120.2,
124.8, 128.2, 134.1, 134.3, 149.8, 150.8, 152.7, 154.7, 156.4.
4.2.1.18. N-(N0-3-(7-chloro-4-quinolyl)aminopropyl)-8-quino-
linesulfonamide, 16. Employing 0.19 g (0.82 mmol) of N-(7-
chloro-4-quinolyl)-1,3-diaminopropane and 8-quinolinesulfonyl
chloride (0.22 g, 0.98 mmol) in the procedure described above gave
0.14 g (0.33 mmol, 40% yield) of white crystals. 1H NMR (300 MHz,
DMSO-d6) d = 1.71 (tt, J = 6.5 Hz, J = 6.5 Hz, 2H), 2.95 (dt, J = 6.5 Hz,
J = 5.8 Hz, 2H), 3.15 (dt, J = 6.5 Hz, J = 6.2 Hz, 2H), 6.23 (d, J = 5.5 Hz,
1H), 7.17 (t, J = 5.8 Hz, 1H), 7.35 (t, J = 6.2 Hz, 1H), 7.42 (dd,
4.2.1.23. N-(3-(7-chloro-4-quinolyl)aminopropyl)-N0-(2-methoxy-
4-nitrophenyl)urea, 20. Employing 0.146 g (0.65 mmol) of N-(7-
chloro-4-quinolyl)-1,3-diaminopropane and 2-methoxy-4-nitro-
phenyl isocyanate (0.1 g, 0.52 mmol) in the procedure described
above gave 0.186 g (0.43 mmol, 83 % yield) of yellow crystals. 1H
NMR (300 MHz, DMSO-d6) d = 1.85–1.90 (m, 2H), 3.25–3.31 (m,

278
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3H), 3.61 (t, J = 6.4 Hz, 1H), 4.00 (s, 3H), 6.51 (d, J = 5.4 Hz, 1H), 7.32
(t, J = 5.3 Hz, 2H), 7.46 (dd, J = 2.2 Hz, J = 8.8 Hz, 1H), 7.78 (dd,
J = 2.2 Hz, J = 10.7 Hz, 2H), 7.88 (dd, J = 2.4 Hz, J = 9.0 Hz, 1H), 8.29
(d, J = 9.3 Hz, 1H), 8.40 (d, J = 3.4 Hz, 1H), 8.43 (s, 1H), 8.57 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d = 28.9, 57.1, 79.9, 106.1,
116.4, 118.2, 118.4, 124.8, 128.2, 134.1, 137.4, 140.9, 147.2,
149.8, 150.7, 152.6, 155.2.
inophenyl isothiocyanate (0.101 g, 0.57 mmol) in the procedure
described above gave 0.157 g (0.38 mmol, 67 % yield) of white
crystals. 1H NMR (300 MHz, DMSO-d6) d = 1.90–1.99 (m, 2H),
2.90 (s, 6H), 3.30–3.38 (m, 2H), 3.61–3.64 (m, 2H), 6.50 (d,
J = 5.4 Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H),
7.36 (t, J = 5.3 Hz, 1H), 7.49 (dd, J = 2.2 Hz, J = 9.0 Hz, 2H), 7.82 (d,
J = 2.2 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.44 (d, J = 5.4, 1H), 9.28 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d = 28.2, 79.9, 113.3, 118.2,
124.7, 126.7, 128.2, 134.0, 149.0, 149.8, 150.7, 152.6, 181.3.
4.2.1.24. N-(3-(7-chloro-4-quinolyl)aminopropyl)-N0-(4-dimeth-
ylaminophenyl)urea, 21. Employing 0.178 g (0.75 mmol) of N-(7-
chloro-4-quinolyl)-1,3-diaminopropane and 4-dimethylaminophe-
nyl isocyanate (0.1 g, 0.62 mmol) in the procedure described above
furnished 0.208 g (0.52 mmol, 84 % yield) of white crystals. 1H
NMR (300 MHz, DMSO-d6) d = 1.81–1.88 (m, 2H), 2.84 (s, 6H),
3.24 (q, J = 6.4 Hz, 2H), 3.31–3.39 (m, 2H), 6.11 (t, J = 5.7 Hz, 1H),
6.52 (d, J = 5.4 Hz, 1H), 6.69 (d, J = 9.0 Hz, 2H), 7.23 (d, J = 9.0 Hz,
2H), 7.37 (t, J = 5.0 Hz, 1H), 7.49 (dd, J = 2.2 Hz, J = 9.0 Hz, 1H),
7.83 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 8.44
(d, J = 5.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d = 2.8, 29.4,
37.8, 67.7, 95.2, 99.3, 113.9, 116.2, 118.2, 120.6, 124.8, 128.2,
131.2, 134.1, 135.5, 138.2, 143.7, 146.8, 149.3, 150.7, 152.6, 156.6.
4.2.1.29. N-(3-(7-chloro-4-quinolyl)aminopropyl)-N0-(4-dimeth
ylaminonaphthyl)thiourea, 26.
N-(7-chloro-4-quinolyl)-1,3-
diaminopropane (0.123 g, 0.52 mmol) and 4-dimethylamino-1-
naphthyl isothiocyanate (0.10 g, 0.44 mmol) were employed in
the procedure described above. The solution was then cooled to -
45 °C and 0.175 g (0.38 mmol, 96 % yield) of white crystals were
obtained. 1H NMR (300 MHz, DMSO-d6) d = 1.92 (bs, 2H), 2.87 (s,
6H), 3.28 (bs, 2H), 3.59–3.66 (m, 2H), 6.43 (s, 1H), 7.12 (d,
J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.48 (dd, J = 2.2 Hz,
J = 9.0 Hz, 1H), 7.54–7.57 (m, 2H), 7.81–7.87 (m, 2H), 8.20–8.27
(m, 2H), 8.40 (d, J = 5.6 Hz, 1H), 9.57 (bs, 1H); 13C NMR (75 MHz,
DMSO-d6) d = 28.1, 45.6, 79.9, 99.3, 118.2, 124.7, 126.1, 128.2,
129.5, 130.4, 132.1, 134.1, 149.8, 150.6, 151.6, 152.6, 167.4, 182.5.
4.2.1.25. N-(3-(7-chloro-4-quinolyl)aminopropyl)-N0-(2-meth-
oxyphenyl)urea, 22. Employing 0.191 g (0.81 mmol) of N-(7-
chloro-4-quinolyl)-1,3-diaminopropane and 2-methoxyphenyl
isocyanate (0.10 mL, 0.75 mmol) in the procedure described above
gave 0.254 g (0.66 mmol, 82 % yield) of white crystals. 1H NMR
(300 MHz, DMSO-d6) d = 1.85–1.89 (m, 2H), 3.23–3.39 (m, 4H),
3.86 (s, 3H), 6.53 (d, J = 5.9 Hz, 1H), 6.84–7.02 (m, 4H), 7.36 (t,
J = 5.1 Hz, 1H), 7.49 (dd, J = 2.2 Hz, J = 8.8 Hz, 1H), 7.83 (d,
J = 2.2 Hz, 1H), 7.94 (s, 1H), 8.14 (dd, J = 2.0 Hz, J = 7.1 Hz, 1H),
8.32 (d, J = 9.0 Hz, 1H), 8.44 (d, J = 5.6 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) d = 25.8, 29.2, 37.7, 67.7, 99.4, 118.2, 118.7, 121.7,
124.7, 128.2, 130.2, 134.1, 148.0, 149.8, 150.8, 152.6, 156.0.
4.2.1.30. N-(7-Chloro-4-quinolyl)-N0-(3-diethylaminopropanoyl)-
1,2-diaminoethane, 27. A mixture of N-(7-chloro-4-quinolyl)-1,2-
diaminoethane (0.1 g, 0.45 mmol), N,N-diethylamino-3-propionic
acid (0.11 g, 0.6 mmol), EDC (0.11 g, 0.6 mmol) and Et3N (0.19
mL, 1.35 mmol) in 4 mL of anhydrous DMF and CHCl3 (1:1 v/v)
was stirred at room temperature for 2 days. Saturated NaHCO3
solution was added to the cooled reaction mixture, which was then
extracted with CH2Cl2, dried over anhydrous MgSO4, and concen-
trated in vacuo. Flash chromatography using EtOH:Et3N (1:0.05
v/v) as the mobile phase afforded 0.10 g (0.44 mmol, 63% yield)
of yellow crystals. 1H NMR (300 MHz, CDCl3) d = 1.05 (t, J =
7.1 Hz, 6H), 2.48 (t, J = 6.1 Hz, 2H), 2.58 (q, J = 7.1 Hz, 4H), 2.69 (t,
J = 6.1 Hz, 2H), 3.30–3.45 (m, 2H), 3.64–3.78 (m, 2H), 6.28 (d,
J = 5.4 Hz,1H), 7.11 (bs, 1H), 7.40 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H),
7.87 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 5.4 Hz,
1H), 9.51 (bs, 1H); 13C NMR (75 MHz, CDCl3) d = 11.6, 32.4, 38.4,
46.3, 46.5, 48.9, 98.2, 117.5, 122.7, 125.7, 128.2, 135.2, 148.9,
150.7, 151.8, 176.2.
4.2.1.26. N-(3-(7-chloro-4-quinolyl)aminopropyl)-N0-(4-meth-
oxyphenyl)thiourea, 23. Employing 0.162 g (0.69 mmol) of N-(7-
chloro-4-quinolyl)-1,3-diaminopropane and 4-methoxyphenyl
isothiocyanate (0.08 mL, 0.58 mmol) in the procedure described
above gave 0.116 g (0.29 mmol, 51 % yield) of white crystals. 1H
NMR (300 MHz, DMSO-d6) d = 1.95–1.99 (m, 2H), 3.35 (q,
J = 6.3 Hz, 2H), 3.38 (bs, 2H), 3.77 (s, 3H), 6.52 (d, J = 5.4 Hz, 1H),
6.93 (dd, J = 2.2 Hz, J = 6.8 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 7.40
(t, J = 5.1 Hz, 1H), 7.50 (dd, J = 2.2 Hz, J = 9.0 Hz, 1H), 7.64 (bs,
1H), 7.83 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.44 (d,
J = 5.4 Hz, 1H), 9.38 (bs, 1H); 13C NMR (75 MHz, DMSO-d6)
d = 25.8, 28.2, 55.9, 67.7, 114.7, 118.2, 124.8, 126.8, 128.0, 132.3,
134.2, 149.6, 150.8, 152.4, 157.3, 181.4.
4.2.1.31. N-(7-Chloro-4-quinolyl)-N0-(3-diethylaminopropanoyl)-
1,3-diaminopropane, 28. A mixture of N-(7-chloro-4-quinolyl)-1,3-
diaminopropane (1.0 g, 4.24 mmol), N,N-diethylamino-3-propionic
acid (0.78 g, 4.3 mmol), EDC (0.98 g, 5.1 mmol) and triethylamine
(1.8 mL, 12.9 mmol) in 30 mL of anhydrous DMF and chloroform
(1:1 v/v) was stirred at room temperature for 2.5 days. The reaction
mixture was concentrated in vacuo, then dissolved in dichloro-
methane and extracted with aqueous NaOH. The combined organic
layers were dried over anhydrous MgSO4 and concentrated in
vacuo. The crude product was purified by flash chromatography
(ethanol:hexanes:triethylamine 1:1:0.05 v/v) to give 0.83 g of
(2.3 mmol, 54% yield) pale yellow crystals. 1H NMR (300 MHz,
CDCl3) d = 1.02 (t, J = 7.1 Hz, 6H), 1.74–1.83 (m, 2H), 2.41 (t,
J = 5.7 Hz, 2H) , 2.53 (q, J = 7.1 Hz, 4H), 2.67 (t, J = 5.9 Hz, 2H),
3.32–3.43 (m, 4H), 6.37 (d, J = 5.6 Hz, 1H), 6.76 (t, J = 5.7 Hz, 1H),
7.36 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 8.02 (d,
J = 9.0 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 9.04 (t, J = 5.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d = 11.8, 28.6, 32.7, 35.7, 39.2, 46.5, 49.2,
98.6, 117.9, 122.5, 125.7, 128.5, 135.4, 149.4, 150.5, 151.9, 174.8.
4.2.1.27. N-(3-(7-chloro-4-quinolyl)aminopropyl)-N0-(2-meth-
oxy-4-nitrophenyl)thiourea, 24. Employing 0.136 g (0.58 mmol)
of N-(7-chloro-4-quinolyl)-1,3-diaminopropane and 2-methoxy-
4-nitrophenyl isothiocyanate (0.101 g, 0.48 mmol) in the proce-
dure described above afforded 0.144 g (0.33 mmol, 76 % yield) of
yellow crystals. 1H NMR (300 MHz, DMSO-d6) d = 1.98–2.03 (m,
2H), 3.36–3.42 (m, 3H), 3.63–3.69 (m, 2H), 4.02 (s, 3H), 6.54 (d,
J = 5.4 Hz, 1H), 7.37 (t, J = 5.3 Hz, 1H), 7.49 (dd, J = 2.4 Hz,
J = 9.0 Hz, 1H), 7.83 (t, J = 2.4 Hz, 2H), 7.90 (dd, J = 2.7 Hz,
J = 9.0 Hz, 3H), 8.31 (d, J = 9.3 Hz, 1H), 8.45 (d, J = 5.4 Hz, 1H),
8.79 (d, J = 9.0 Hz , 1H), 9.13 (bs, 1H); 13C NMR (75 MHz, DMSO-
d6) d = 27.7, 42.5, 57.2, 79.9, 106.5, 116.8, 118.2, 124.8, 128.2,
134.1, 136.1, 142.9, 149.8, 150.7, 152.7, 180.5.
4.2.1.28. N-(3-(7-chloro-4-quinolyl)aminopropyl)-N0-(4-dimeth-
ylaminophenyl)thiourea, 25. Employing 0.159 g (0.67 mmol) of
N-(7-chloro-4-quinolyl)-1,3-diaminopropane and 4-dimethylam-
4.2.1.32. N-(7-Chloro-4-quinolyl)-N0-(3-diethylaminopropanoyl)-
1,4-diaminobutane, 29. A mixture of N-(7-chloro-4-quinolyl)-1,4-
diaminobutane (2.0 g, 8.0 mmol), N,N-diethylamino-3-propionic

K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
279
acid (1.45 g, 8.0 mmol), EDC (1.84 g, 9.6 mmol), and triethylamine
(3.35 mL, 24.0 mmol) in 80 mL of anhydrous DMF and chloroform
(1:1 v/v) was stirred at room temperature for 2.5 days. The reaction
mixture was concentrated in vacuo and partitioned between
dichloromethane and 1 N NaOH solution. The combined organic
layers were dried over anhydrous Na2SO4 and concentrated in va-
cuo. The crude product was purified by flash chromatography
(methanol:ammonium hydroxide 1.0:0.005 v/v) to give 1.8 g
(4.8 mmol, 60% yield) of colorless crystals. 1H NMR (300 MHz,
CDCl3) d = 1.02 (t, J = 7.2 Hz, 6H), 1.60–1.88 (m, 4H), 2.36 (t,
J = 6.0 Hz, 2H), 2.54 (q, J = 7.2 Hz, 4H), 2.65 (t, J = 6.0 Hz, 2H),
3.28–3.42 (m, 4H), 5.71 (bt, 1H), 6.38 (d, J = 5.7 Hz, 1H), 7.35 (dd,
J = 2.4 Hz, J = 9.0 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.93 (d,
J = 2.4 Hz, 1H), 8.51 (d, J = 5.7 Hz, 1H), 8.85 (bt, 1H); 13C NMR
(75 MHz, CDCl3) d = 11.3, 25.2, 27.8, 32.3, 38.1, 42.9, 45.8, 48.6,
98.6, 117.3, 121.9, 124.7, 128.0, 134.4, 148.9, 150.0, 151.6, 173.1.
CH2Cl2, extracted with water, dried over anhydrous Na2SO4 and
concentrated in vacuo. Flash chromatography (MeOH:EtOAc 1:32
v/v) allowed the isolation of 0.2 g of 32 (0.41 mmol, 73% yield) as
light brown crystals.
4.2.1.36. N-(7-Chloro-4-quinolyl)-N0-(2-naphthylaminobenzoyl)-
1,3-diaminopropane, 32. 1H NMR (300 MHz, CDCl3) d = 1.91 (m,
2H), 3.37 (q, J = 5.7 Hz, 2H), 3.58 (q, J = 6.3 Hz, 2H), 6.32 (d,
J = 5.7 Hz, 1H), 6.46 (t, J = 5.7 Hz, 1H), 6.71 (m, 1H), 6.97 (bs, 1H),
7.16–7.28 (m, 3H), 7.38–7.56 (m, 5H), 7.62 (d, J = 8.1 Hz, 1H),
7.84–7.95 (m, 3H), 8.17 (m, 1H), 8.42 (d, J = 5.7 Hz, 1H), 9.90 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d = 27.6, 37.1, 40.2, 98.5, 98.7,
114.8, 115.7, 117.4, 117.8, 118.1, 121.4, 122.6, 124.0, 126.0,
126.2, 127.2, 127.3, 128.4, 128.7, 131.9, 133.4, 134.3, 137.1,
145.4, 148.8, 150.1, 151.6, 169.3.
4.2.1.37. N-(7-Chloro-4-quinolyl)-N0-(2-benzylamino-4-fluoro-
benzoyl)-1,3-diaminopropane, 33. Employing 0.15 g (0.6 mmol)
of 4-fluoro-N-benzylanthranilic acid and N-(7-chloro-4-quinolyl)-
1,3-diaminopropane (0.43 g, 1.83 mmol) in the procedure
described above and purification by flash chromatography (MeO-
H:EtOAc 1:49 v/v) gave 0.16 g (0.35 mmol, 59% yield) of colorless
crystals. 1H NMR (300 MHz, CD3OD) d = 2.00 (m, 2H), 3.40–3.54
(m, 4H), 4.31 (s, 2H), 6.23–6.38 (m, 2H), 6.52 (d, J = 5.7 Hz, 1H),
7.18–7.38 (m, 6H), 7.50 (dd, J = 2.1 Hz, 9.0 Hz, 1H), 7.75 (d,
J = 2.1 Hz, 1H), 8.05 (d, J = 9.0 Hz, 1H), 8.31 (d, J = 5.7 Hz, 1H); 13C
NMR (75 MHz, DMSO-d6) d = 27.7, 36.8, 36.9, 45.9, 46.0, 97.5,
97.9, 98.6, 100.8, 101.1, 111.8, 117.4, 117.5, 124.0, 126.9, 127.1,
127.4, 128.5, 130.6, 130.8, 133.3, 138.9, 149.0, 149.9, 150.0,
151.1, 151.2, 151.3, 151.4, 151.8, 163.3, 166.5, 168.4, 168.4, 168.5.
4.2.1.33. N-(7-Chloro-4-quinolyl)-N0-(3-diethylaminopropanoyl)-
1,5-diaminopentane, 30. A mixture of N-(7-chloro-4-quinolyl)-1,5-
diaminopentane (0.25 g, 0.95 mmol), N,N-diethylamino-3-propionic
acid (0.17 g, 0.93 mmol), EDC (0.22 g, 1.14 mmol), and triethyl-
amine (0.4 mL, 2.9 mmol) in 12 mL of anhydrous DMF and chloro-
form (1:1 v/v) was stirred at room temperature for 2.5 days. The
reaction mixture was concentrated in vacuo, then dissolved in
dichloromethane and extracted with aqueous NaOH. The com-
bined organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (methanol:ammonium hydroxide 1.0:0.05 v/v)
to afford 0.045 g (0.11 mmol, 12% yield) of colorless crystals. 1H
NMR (300 MHz, CDCl3) d = 1.01 (t, J = 7.2 Hz, 6H), 1.49–1.59 (m,
4H), 1.82–1.87 (m, 2H) , 2.53 (t, J = 6.0 Hz, 2H), 2.53 (q, J = 7.2 Hz,
4H), 2.64 (t, J = 6.0 Hz, 2H), 3.26–3.33 (m, 4H), 5.46 (bs, 1H), 6.37
(d, J = 5.4 Hz, 1H), 7.35 (dd, J = 2.2 Hz, 8.8 Hz, 1H), 7.94 (d,
J = 2.2 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 5.4 Hz, 1H),
8.80 (bs, 1H); 13C NMR (75 MHz, CDCl3) d = 11.8, 24.3, 28.0, 30.0,
32.8, 37.9, 43.4, 46.3, 49.2, 100.6, 117.6, 122.0, 128.9, 134.9,
149.5, 150.3, 152.3, 173.7.
4.2.1.38. N-(7-Chloro-4-quinolyl)-N0-(2-phenylethylaminoben-
zoyl)-1,3-diaminopropane, 34. Employing 0.15 g (0.6 mmol) of N-
phenethylanthranilic acid and N-(7-chloro-4-quinolyl)-1,3-diami-
nopropane (0.44 g, 1.86 mmol) in the procedure described above
and purification by flash chromatography (MeOH:EtOAc 1:24 v/v)
gave 0.19 g (0.42 mmol, 68% yield) of colorless crystals. 1H NMR
(300 MHz, CD3OD) d = 1.98 (m, 2H), 2.90 (t, J = 7.2 Hz, 2H), 3.36–
3.52 (m, 6H), 6.50 (d, J = 5.7 Hz, 1H), 6.59 (m, 1H), 6.74 (d,
J = 8.1 Hz, 1H), 7.13 (m, 1H), 7.20–7.48 (m, 7H), 7.78 (d,
J = 2.4 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 8.33 (d, J = 5.7 Hz, 1H); 13C
NMR (75 MHz, DMSO-d6) d = 22.7, 34.8, 36.8, 43.8, 43.9, 79.1,
98.6, 111.0, 114.1, 115.0, 115.1, 115.2, 117.4, 117.5, 124.0, 126.0,
127.4, 128.2, 128.8, 132.3, 133.4, 139.4, 148.7, 148.8, 148.9,
149.9, 150.0, 151.7, 169.1, 169.1, 169.2, 169.2.
4.2.1.34. N-(7-Chloro-4-quinolyl)-N0-(3-diethylaminopropanoyl)-
1,6-diaminohexane, 31. A mixture of N-(7-chloro-4-quinolyl)-1,6-
diaminohexane (0.1 g, 0.36 mmol), N,N- diethylamino-3-propionic
acid (0.08 g, 0.43 mmol), EDC (0.08 g, 0.43 mmol) and Et3N (0.19
mL, 1.35 mmol) was stirred at room temperature in 4 mL of
DMF:CHCl3 (1:1 v/v) for 2 days. Saturated NaHCO3 was added to
the cooled reaction mixture, which was then extracted with CH2Cl2
and dried over anhydrous MgSO4, and concentrated in vacuo. Puri-
fication by flash chromatography using EtOH:Et3N (1:0.05 v/v) as
the mobile phase gave yellow crystals (0.12 g, 0.27 mmol, 76%
yield). 1H NMR (300 MHz, CDCl3) d = 1.06 (t, J = 7.1 Hz, 6H), 1.25–
1.62 (m, 6H), 1.63–1.82 (m, 2H), 2.40 (t, J = 6.1 Hz, 2H), 2.58 (q,
J = 7.1 Hz, 4H), 2.69 (t, J = 6.1 Hz, 2H), 3.20–3.41 (m, 4H), 5.37 (bs,
1H), 6.41 (d, J = 5.4 Hz, 1H), 7.38 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H),
7.80 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 8.53 (d, J = 5.4 Hz,
1H), 8.67 (bs, 1H); 13C NMR (75 MHz, CDCl3) d = 11.7, 26.7, 28.7,
29.8, 32.7, 38.7, 43.1, 46.3, 49.2, 99.1, 117.5, 121.9, 125.3, 128.6,
135.0, 149.2, 150.3, 152.0, 173.2.
4.2.1.39. N-(7-Chloro-4-quinolyl)-N0-(2-cyclohexylthiobenzoyl)-
1,3-diaminopropane, 35. Employing 0.12 g (0.51 mmol) of
2-(cyclohexylthio)benzoic acid and N-(7-chloro-4-quinolyl)-1,3-
diaminopropane (0.1 g, 0.43 mmol) in the procedure described
above (this reaction was conducted at 70 °C) and purification by
flash chromatography (MeOH:CH2Cl2 1:49 v/v and gradually
changing the ratio of MeOH:CH2Cl2 to 1:11.5 v/v) gave 0.07 g
(0.15 mmol, 35% yield) of light yellow crystals. 1H NMR
(300 MHz, CDCl3) d = 1.12–1.44 (m, 5H), 1.59 (s, 1H), 1.72 (m,
2H), 1.85–2.04 (m, 4H), 3.11 (m, 1H), 3.50–3.70 (m, 4H), 6.41 (d,
J = 5.4 Hz, 1H), 6.77 (bt, 1H), 7.29–7.53 (m, 5H), 7.75 (dd,
J = 7.5 Hz, J = 2.1 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 8.02 (d,
J = 9.0 Hz, 1H), 8.46 (d, J = 5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d = 25.2, 25.8, 28.1, 33.1, 36.5, 39.0, 48.0, 98.2, 98.3, 117.5, 122.2,
125.3, 127.4, 127.8, 129.2, 130.5, 132.0, 134.0, 135.0, 138.0,
148.7, 150.2, 151.2, 151.3, 169.6.
4.2.1.35. Representative procedure for the synthesis of amide
analogs 32–36. To a solution of N-(1-naphthyl)anthranilic acid
(0.15 g, 0.57 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine
(CDMT) (0.1 g, 0.57 mmol) in anhydrous CHCl3, 0.1 mL (0.63 mmol)
of N-methylmorpholine (NMM) was added dropwise at 0 °C and
stirred at room temperature for 2 h. N-(7-Chloro-4-quinolyl)-1,3-
diaminopropane (0.41 g, 1.7 mmol) in anhydrous DMF was then
added. The reaction mixture was stirred for another 2 h and con-
centrated under reduced pressure. The residue was dissolved in
4.2.1.40. N-(7-Chloro-4-quinolyl)-N0-(2-phenylthiobenzoyl)-1,3-
diaminopropane, 36. Employing 0.12 g (0.51 mmol) of 2-(phenyl-
thio)benzoic acid and N-(7-chloro-4-quinolyl)-1,3-diaminopropane

280
K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
(0.1 g, 0.43 mmol) in the procedure described above (this reaction
was conducted at 70 °C) and purification by flash chromatography
(MeOH:CH2Cl2 1:24 v/v) gave 0.05 g (0.1 mmol, 25% yield) of light
yellow crystals. 1H NMR (300 MHz, CDCl3) d = 1.84 (m, 2H), 3.42 (q,
J = 6.0 Hz, 2H), 3.54 (q, J = 6.0 Hz, 1H), 6.36 (d, J = 5.4 Hz, 1H), 6.60
(t, J = 6.0 Hz, 1H), 6.89 (t, J = 6.0 Hz, 1H), 7.22–7.39 (m, 9H), 7.66
(m, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 8.44 (d,
J = 5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) d = 28.0, 36.6, 38.8,
98.2, 98.3, 117.5, 122.1, 125.2, 125.3, 127.3, 127.7, 128.0, 128.1,
128.8, 129.5, 131.0, 131.2, 132.3, 133.7, 134.3, 134.9, 136.5,
148.9, 150.0, 151.4, 151.5, 169.3.
4.2.1.45. N-(7-Chloro-4-quinolyl)-N0-(3-pyridoyl)-1,3-diamino-
propane, 41. Employing 0.1 g (0.43 mmol) of N-(7-chloro-4-quino-
lyl)-1,3-diaminopropane and 3-nicotinic acid (0.064 g, 0.52 mmol)
in the procedure described above and purification by flash chroma-
tography using EtOH:Et3N (1:0.02 v/v) as mobile phase afforded a
colorless oil (0.032 g, 0.084 mmol, 20% yield). 1H NMR (300 MHz,
CDCl3) d = 2.01–2.72 (m, 2H), 3.51 (t, J = 6.9 Hz, 2H), 3.75 (t,
J = 6.9 Hz, 2H), 6.66 (d, J = 8.4 Hz, 1H), 7.45–7.60 (m, 2H), 7.82
(dd, J = 2.1 Hz, J = 5.8 Hz, 1H), 8.24–8.31 (m, 2H), 8.39 (d,
J = 2.1 Hz, 1H), 8.71 (dd, J = 2.1 Hz, J = 5.8 Hz, 1H), 9.10 (d,
J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) d = 28.2, 38.7, 39.5,
98.2, 116.3, 119.4, 123.6, 124.7, 127.3, 129.5, 133.9, 134.1, 134.7,
147.4, 147.8, 151.0, 151.7, 166.4.
4.2.1.41. Representative procedure for the synthesis of amide
analogs
(37–44). N-(7-Chloro-4-quinolyl)-1,3-diaminopropane
(0.1 g, 0.43 mmol), Boc-Trp-OH (0.16 g, 0.52 mmol) and 2-chloro-
4,6-dimethoxy-1,3,5-triazine (CDMT) (0.09 g, 0.52 mmol) were
dissolved in 3 mL of acetonitrile and 1 mL of DMF. N-Methylmor-
pholine (NMM) (0.165 g, 0.65 mmol) was added and the reaction
was stirred at 40 °C for 24 h. The solvents were removed under
reduced pressure and dissolved in 25 mL of CH2Cl2 and washed
twice with 1 mL of water and brine, respectively. The combined or-
ganic layers were dried over anhydrous MgSO4 and concentrated in
vacuo. Purification by flash chromatography using EtOAc:EtO-
H:Et3N (4:1:0.02 v/v) as the mobile phase gave 0.134 g of 37 as a
colorless oil (0.26 mmol, 60% yield) from Boc-D-Trp-OH. The same
procedure gave 0.09 g of 38 as a colorless oil (0.17 mmol, 40%
yield) from Boc-Trp-OH.
4.2.1.46. N-(7-Chloro-4-quinolyl)-N0-[3-(6-hydroxypyridoyl]-
1,3-diaminopropane, 42. Employing 0.1 g (0.43 mmol) of N-(7-
chloro-4-quinolyl)-1,3-diaminopropane and 6-hydroxynicotinic
acid (0.075 g, 0.52 mmol) in the procedure described above and
purification by flash chromatography using EtOH:Et3N (1:0.02 v/
v) as mobile phase gave a colorless oil (0.038 g, 0.11 mmol, 25%
yield). 1H NMR (300 MHz, CDCl3) d = 1.82–1.98 (m, 2H), 3.62 (t,
J = 6.7 Hz, 2H), 3.79 (t, J = 6.7 Hz, 2H), 6.42 (d, J = 7.5 Hz, 1H), 7.15
(d, J = 6.8 Hz, 1H), 7.24–7.38 (m, 2H), 8.21 (d, J = 7.5 Hz, 1H), 8.32
(d, J = 6.8 Hz, 1H), 8.42 (dd, J = 2.0 Hz, J = 5.4 Hz, 1H), 8.91 (d,
J = 2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d = 28.4, 38.3, 39.6,
98.2, 110.9, 114.7, 119.4, 116.5, 124.6, 129.5, 134.0, 145.2,
149.8,151.8, 154.1, 154.7, 166.7.
4.2.1.42. N-(7-Chloro-4-quinolyl)-N0-1,3-diaminopropan-N00-t-
Boc-tryptophan amide, 37 and 38. 1H NMR (300 MHz, CDCl3)
d = 1.40 (s, 9H), 2.74–2.92 (m, 4H), 1.65–1.84 (m, 2H), 3.18–3.36
(m, 6H), 4.34 (t, J = 6.0 Hz, 1H), 6.36 (d, J = 5.6 Hz, 1H), 6.89–7.11
(m, 3H), 7.12 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.40 (dd, J = 2.0 Hz,
J = 7.2 Hz,1H), 7.77 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 8.31
(d, J = 6.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d = 27.5, 28.2, 36.6,
39.7, 56.2, 78.3, 79.5, 98.5, 109.8, 111.2, 117.6, 118.3, 118.7,
121.3, 123.1, 123.4, 124.8, 126.4, 127.7, 135.1, 136.9, 148.4,
151.3, 156.4, 174.0.
4.2.1.47. N-(7-Chloro-4-quinolyl)-N0-(3-dimethylaminobenzoyl)-
1,3-diaminopropane, 43. Employing 0.1 g (0.43 mmol) of
N-(7-chloro-4-quinolyl)-1,3-diaminopropane and 3-dimethylami-
nobenzoic acid (0.086 g, 0.52 mmol) in the procedure described
above and purification by flash chromatography using CH2Cl2:EtO-
H:Et3N (1:1:0.02 v/v) as the mobile phase gave a colorless oil
(0.042 g, 0.11 mmol, 25% yield). 1H NMR (300 MHz, CDCl3)
d = 1.95–2.18 (m, 2H), 3.47 (t, J = 6.8 Hz, 2H), 3.55 (t, J = 6.8 Hz,
2H), 3.96 (s, 6H), 6.55 (d, J = 5.7 Hz, 1H), 7.36–7.42 (m, 2H), 7.53
(dd, J = 6.3 Hz, J = 7.5 Hz, 1H), 7.70 (dd, J = 2.1 Hz, J = 6.3 Hz, 1H),
7.75 (d, J = 2.1 Hz, 2H), 8.12 (d, J = 9 Hz, 1H), 8.32 (d, J = 5.7 Hz,
1H); 13C NMR (75 MHz, CDCl3) d = 27.8, 39.4, 39.6, 40.7, 40.9,
98.7, 108.5, 116.3, 116.9, 120.6, 129.1, 134.4, 134.8, 148.5, 150.9,
151.7, 166.8.
4.2.1.43. N-(7-Chloro-4-quinolyl)-N0-1,3-diaminopropan-N00-Z-
lysine amide, 39. Employing 0.1 g (0.43 mmol) of N-(7-chloro-4-
quinolyl)-1,3-diaminopropane and Z-Lys(Boc)-OH (0.198 g, 0.52
mmol) in the procedure described above and purification by flash
chromatography using EtOAc:EtOH:Et3N (1:1:0.02 v/v) as the
mobile phase gave a colorless oil (0.077 g, 0.13 mmol, 30% yield).
1H NMR (300 MHz, CDCl3) d = 1.42 (s, 9H), 1.61–1.98 (m, 6H),
2.95 (m, 1H), 3.01–3.18 (m, 2H), 3.22–3.45 (m, 4H), 4.11–4.25
(m, 1H), 4.83 (t, J = 6.0 Hz, 1H), 5.10 (s, 2H), 6.12 (d, J = 6.3 Hz,
1H), 6.48 (d, J = 5.6 Hz,1H), 7.25–7.40 (m, 5H), 7.92 (d, J = 2.2 Hz,
1H), 7.93 (d, J = 9.0 Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d = 22.8, 28.2, 28.7, 29.9, 31.9, 36.5, 39.3, 39.8,
55.6, 67.5, 79.6, 98.7, 117.8, 122.4, 125.5, 128.3, 128.5, 128.8,
135.1, 136.4, 149.4, 150.3, 152.2, 156.7, 156.8, 162.9, 173.7.
4.2.1.48. N-(7-Chloro-4-quinolyl)-N0-[3-(2-benzimidazol)propa-
noyl]-1,3-diaminopropane, 44. Employing 0.1 g (0.43 mmol) of
N-(7-chloro-4-quinolyl)-1,3-diaminopropane and 2-benzimidaz-
olepropionic acid (0.1 g, 0.52 mmol) in the procedure described
above and purification by flash chromatography using EtOH:Et3N
(1:0.01 v/v) as mobile phase gave
a colorless oil (0.061 g,
0.15 mmol, 35% yield) . 1H NMR (300 MHz, MeOD) d = 1.78–1.95
(m, 2H), 2.27 (t, J = 7.2 Hz, 2H), 3.21 (t, J = 7.5 Hz, 2H), 3.25 (t,
J = 7.5 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H), 6.38 (d, J = 5.7 Hz, 1H),
7.10–7.18 (m, 2H), 7.37 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H), 7.42–7.51
(m, 2H), 8.05 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 8.28 (d,
J = 5.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) d = 24.5, 27.8, 33.5,
36.6, 39.9, 98.4, 117.4, 122.1, 123.3, 125.1, 125.4, 135.4, 135.7,
147.2, 150.1, 152.0, 154.3, 173.3.
4.2.1.44. N-(7-Chloro-4-quinolyl)-N0-1,3-diaminopropan-N00-t-
Boc-proline amide, 40. Employing 0.1 g (0.43 mmol) of N-(7-
chloro-4-quinolyl)-1,3-diaminopropane and Boc-Pro-OH (0.112 g,
0.52 mmol) in the procedure described above and purification by
flash chromatography using EtOH:Et3N (1:0.02 v/v) as the mobile
phase gave a colorless oil (0.092 g, 0.24 mmol, 55% yield). 1H
NMR (300 MHz, CDCl3) d = 1.45 (s, 9H), 1.82–2.10 (m, 6H), 3.36–
3.62 (m, 6H), 4.18–4.22 (m, 1H), 6.62 (d, J = 9.0 Hz, 1H), 7.44 (dd,
J = 2.2 Hz, J = 6.8 Hz, 1H), 7.81 (d, J = 2.2 Hz, 1H), 8.17 (d,
J = 9.0 Hz, 1H), 8.38 (d, J = 6.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d = 24.6, 28.1, 28.4, 36.0, 38.9, 47.2, 60.3, 80.6, 98.2, 117.4, 122.2,
125.5, 127.6, 135.3, 148.3, 150.4, 150.9.
4.2.1.49. N-(7-Chloro-4-quinolyl)-N0-(2,5-diaminobenzoyl)-1,3-
diaminopropane, 45. A mixture of 5-aminoisatoic anhydride
(0.1 g, 0.56 mmol) and N-(7-chloro-4-quinolyl)-1,3-diaminopro-
pane (0.15 g, 0.67 mmol) in ethanol was refluxed for 24 h. After
cooling to room temperature, the filtrate was concentrated under
reduced pressure. The residue was purified using flash chromatog-
raphy (MeOH:CH2Cl2 3:7 v/v) to afford 0.13 g (0.34 mmol, 64%
yield) of brown crystals. 1H NMR (300 MHz, CD3OD) d = 1.95 (m,

K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
281
2H), 3.36 (t, J = 6.9 Hz, 1H), 3.43 (t, J = 6.9 Hz, 1H), 6.42 (d,
J = 6.0 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 6.74 (dd, J = 2.4 Hz,
J = 8.7 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 2.1 Hz,
J = 9.0 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H),
8.26 (d, J = 6.0 Hz, 1H); 13C NMR (75 MHz, CD3OD) d = 29.2, 38.1,
41.3, 99.5, 115.9, 118.6, 119.8, 120.0, 122.4, 124.2, 125.9, 127.2,
136.3, 139.0, 141.8, 149.1, 152.0, 152.5, 172.1.
118.7, 124.2, 126.0, 127.5, 127.6, 136.3, 138.9 (m), 143.3 (m),
145.0 (m), 149.5, 152.3, 152.5, 159.8.
4.2.1.54. N-(7-Chloro-4-quinolyl)-N0-(heptafluorobutyryl)-1,3-
diaminopropane, 49. Using 0.11 g (0.47 mmol) of N-(7-chloro-4-
quinolyl)-1,3-diaminopropane and perfluorobutyryl chloride
(0.08 mL, 0.51 mmol) in the procedure described above and purifi-
cation by flash chromatography with MeOH:CH2Cl2 (1:16 v/v), fol-
lowed by extraction with 1 N NaOH gave 0.1 g (0.23 mmol, 49%
yield) of off-white crystals. 1H NMR (300 MHz, CD3OD) d = 1.98
(m, 2H), 3.39 (t, J = 7.2 Hz, 2H), 3.45 (t, J = 7.2 Hz, 2H), 6.50 (d,
J = 5.7 Hz, 1H), 7.39 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H), 7.76 (d,
J = 2.1 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 8.34 (d, J = 5.7 Hz, 1H); 19F
NMR (282 MHz, CD3OD) d = ꢁ82.6 (t, J = 9.0 Hz, 3F), ꢁ122.2 (q, J =
9.0 Hz, 2F), ꢁ128.7 (s, 2F); 13C NMR (75 MHz, CD3OD) d = 28.6,
38.7, 41.1, 99.5, 99.6, 105.8–114.2 (m), 117.1 (t, JC-F = 141.0 Hz),
118.7, 120.9 (t, JC-F = 141.0 Hz), 124.1, 126.0, 126.0, 127.4, 127.5,
136.3, 149.4, 152.2, 152.5, 159.4 (t, JC-F = 95.9 Hz).
4.2.1.50. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]-2-benzylamino-4-fluorobenzamide, 46. Employing
0.034 g (0.14 mmol) of 4-fluoro-N-benzylanthranilic acid and N-
(7-chloro-4-quinolyl)-N0-ethyl-N0-(2-aminoethyl)-1,2-diaminoe-
thane 10 (0.04 g, 0.14 mmol) in the procedure described for the
syntheses of 32–36 followed by flash chromatography using
MeOH:CH2Cl2 (1:49 to 1:15 v/v) as the mobile phase gave
0.047 g (0.09 mmol, 66% yield) of a light yellow oil. 1H NMR
(300 MHz, CD3OD) d = 1.10 (t, J = 6.9 Hz, 3H), 2.64–2.78 (m, 4H),
2.85 (t, J = 6.3 Hz, 2H), 3.34–3.47 (m, 4H), 3.55 (t, J = 6.9 Hz, 2H),
6.40 (d, J = 5.7 Hz, 1H), 7.24 (dd, J = 1.8 Hz, J = 9.0 Hz, 1H), 7.66
(d, J = 1.8 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 8.08 (s, 1H), 8.24 (d,
J = 5.7 Hz, 1H), 8.38 (s, 2H); 19F NMR (282 MHz, CDCl3)
d = ꢁ62.9; 13C NMR (75 MHz, CD3OD) d = 12.2, 38.5, 41.5, 47.8,
52.4, 53.5, 98.8 (m), 99.8, 99.9, 102.5 (m), 113.1, 118.5, 123.9,
126.0, 127.2, 127.3, 128.2, 129.6, 131.2 (dd, JC-F = 6.8 Hz,
JC-F = 22.6 Hz), 136.4, 136.9, 149.0, 152.0, 152.5, 152.6, 152.7,
165.4, 168.7, 171.3.
4.2.1.55. N-(7-Chloro-4-quinolyl)-N0-(pentadecafluorooctanoyl)-
1,3-diaminopropane, 50. Employing 0.15 g (0.64 mmol) of N-(7-
chloro-4-quinolyl)-1,3-diaminopropane and pentadecafluorooctanoyl
chloride (0.17 mL, 0.7 mmol) in the procedure described above and
purification by flash chromatography using MeOH:CH2Cl2 (1:19 to
1:9 v/v), followed by extraction with 1 N NaOH gave 0.1 g
(0.16 mmol, 25% yield) of off-white crystals. 1H NMR (300 MHz,
CD3OD) d = 1.99 (m, 2H), 3.40 (t, J = 7.2 Hz, 2H), 3.45 (t, J = 6.9 Hz,
2H), 6.50 (d, J = 6.0 Hz, 1H), 7.39 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H),
7.77 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H), 8.34 (d, J = 6.0 Hz,
1H); 19F NMR (282 MHz, CDCl3) d = –78.8 (tt, J = 2.5 Hz, J = 9.9 Hz,
3F), ꢁ117.1 (t, J = 12.5 Hz, 2F), ꢁ118.9 (m, 2F), ꢁ119.4 (m, 2F),
ꢁ120.1 (m, 2F), ꢁ123.7 (m, 2F); 13C NMR (75 MHz, CD3OD)
4.2.1.51. Representative procedure for the synthesis of amide
analogs 47–50. To a solution of N-(7-chloro-4-quinolyl)-1,3-
diaminopropane (0.11 g, 0.47 mmol) and Et3N (0.13 mL, 0.94
mmol) in anhydrous DMF and CHCl3 (1:1 v/v), 3,5-bis(trifluoro-
methyl)benzoyl chloride (0.092 mL, 0.51 mmol) was added at
0 °C. The reaction mixture was stirred for 3 h at room temperature
and concentrated under reduced pressure. Saturated NaHCO3 solu-
tion was added to the residue, which was then extracted with
CH2Cl2, dried over anhydrous Na2SO4, and concentrated in vacuo.
Flash chromatography using MeOH:CH2Cl2 (1:19 to 1:9 v/v) gave
0.224 g of the N-acyl quinolinium salt of 47. The crystalline residue
was hydrolyzed in 1 N NaOH solution, extracted with CH2Cl2, dried
over anhydrous Na2SO4, and concentrated in vacuo to yield 0.13 g
(0.27 mmol, 59% yield) of off-white crystals.
d = 28.6, 38.8, 41.2, 106.8–117.2 (m), 118.7, 120.3 (t, JC-F
=
112.8 Hz), 124.1, 126.0, 126.1, 127.5, 127.6, 136.3, 149.6, 152.3,
152.4, 159.5 (t, JC-F = 96.9 Hz).
4.2.1.56. Representative procedure for the synthesis of amide
analogs 51–54. To a solution of N-(7-chloro-4-quinolyl)-N0-ethyl-
N0-(2-aminoethyl)-1,2-diaminoethane 10 (0.031 g, 0.11 mmol)
and Et3N (0.03 mL, 0.22 mmol) in anhydrous CH2Cl2, 3,5-bis(tri-
fluoromethyl)benzoyl chloride (0.02 mL, 0.11 mmol) was added
at 0 °C. The reaction mixture was stirred for 1 h at room tempera-
ture until saturated 1 N NaOH solution was added. The mixture
was extracted with CH2Cl2, and the combined organic layers were
dried over anhydrous Na2SO4, and concentrated in vacuo. Flash
chromatography using MeOH:CH2Cl2 (1:99 v/v) as the mobile
phase gave 0.051 g of the N-acyl quinolinium salt. The residue
was refluxed in 5 mL of methanol for 6 h and concentrated under
reduced pressure. Flash chromatography using MeOH:CH2Cl2
(1:49 v/v) gave 0.022 g (0.04 mmol, 39% yield) of a yellow oil.
4.2.1.52. N-(7-Chloro-4-quinolyl)-N0-{bis(trifluoromethyl)ben-
zoyl}-1,3-diaminopropane, 47. 1H NMR (300 MHz, CD3OD)
d = 2.03 (m, 2H), 3.37 (t, J = 6.9 Hz, 2H), 3.55 (t, J = 6.9 Hz, 2H),
6.40 (d, J = 5.7 Hz, 1H), 7.24 (dd, J = 1.8 Hz, J = 9.0 Hz, 1H), 7.66 (d,
J = 1.8 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 8.08 (s, 1H), 8.24 (d,
J = 5.7 Hz, 1H), 8.38 (s, 2H); 19F NMR (282 MHz, CDCl3) d = ꢁ62.9
(s, 6F); 13C NMR (75 MHz, CD3OD) d = 27.7, 37.9, 40.2, 98.3, 98.4,
117.4, 117.9, 121.5, 122.9, 124.7, 124.8, 125.1, 126.3, 126.4,
127.7, 128.7, 131.8 (q, JC-F = 126.0 Hz), 135.0, 136.7, 148.3, 151.0,
151.1, 151.2, 165.5.
4.2.1.57. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]-3,5-(bistrifluoromethyl)benzamide, 51. 1H NMR
(300 MHz, CD3OD) d = 1.13 (t, J = 7.2 Hz, 3H), 2.70–2.85 (m, 4H),
2.88 (t, J = 6.3 Hz, 2H), 3.40 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 6.0 Hz,
2H), 6.49 (d, J = 5.7 Hz, 1H), 7.19 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H),
7.67 (d, J = 2.1 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.99 (s, 1H), 8.24
(s, 2H), 8.29 (d, J = 5.7 Hz, 1H); 19F NMR (282 MHz, CDCl3)
d = ꢁ63.3 (s, 6F); 13C NMR (75 MHz, CD3OD) d = 12.2, 39.2, 41.4,
52.5, 53.4, 99.7, 99.8, 118.3, 119.0, 122.6, 123.7, 126.0 (m), 127.3,
127.4, 128.6, 129.8, 132.8 (q, JC-F = 126.0 Hz), 136.3, 137.7, 149.1,
152.2, 152.3, 166.4.
4.2.1.53. N-(7-Chloro-4-quinolyl)-N0-(pentafluorobenzoyl)-1,3-
diaminopropane, 48. Using 0.11 g (0.47 mmol) of N-(7-chloro-4-
quinolyl)-1,3-diaminopropane and 2,3,4,5,6-pentafluorobenzoyl
chloride (0.07 mL, 0.51 mmol) in the procedure described above
and purification by flash chromatography with MeOH:CH2Cl2
(1:19 to 1:9 v/v), followed by extraction with 1 N NaOH gave
0.13 g (0.3 mmol, 65% yield) of off-white crystals. 1H NMR
(300 MHz, CD3OD) d = 2.03 (m, 2H), 3.46 (t, J = 7.2 Hz, 2H), 3.54
(t, J = 6.9 Hz, 2H), 6.53 (d, J = 5.4 Hz, 1H), 7.38 (dd, J = 2.1 Hz,
J = 9.0 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H),
8.34 (d, J = 5.4 Hz, 1H); 19F NMR (282 MHz, CD3OD) d = ꢁ144.4
(m, 2F), ꢁ155.5 (tt, J = 2.5 Hz, J = 19.7 Hz, 1F), ꢁ164.0 (m, 2F); 13C
NMR (75 MHz, CD3OD) d = 28.9, 38.7, 41.2, 99.5, 99.6, 113.4 (m),
4.2.1.58. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]pentafluorobenzamide, 52. Employing 0.047 g (0.16
mmol) of N-(7-chloro-4-quinolyl)-N0-ethyl-N0-(2-aminoethyl)-1,2-

282
K. Ekoue-Kovi et al. / Bioorg. Med. Chem. 17 (2009) 270–283
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diaminoethane 10 and 2,3,4,5,6-pentafluorobenzoyl chloride
(0.023 mL, 0.16 mmol) in the procedure described above and puri-
fication by flash chromatography using MeOH:EtOAc (1:24 v/v) as
the mobile phase gave 0.018 g (0.04 mmol, 23% yield) of light yel-
low crystals. 1H NMR (300 MHz, CD3OD + CDCl3) d = 1.13 (t,
J = 6.9 Hz, 3H), 2.66–2.82 (m, 4H), 2.89 (t, J = 6.3 Hz, 2H), 3.38 (t,
J = 5.7 Hz, 2H), 3.52 (t, J = 6.0 Hz, 2H), 6.43 (d, J = 5.7 Hz, 2H), 7.30
(dd, J = 2.1 Hz, J = 9.0 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.83 (d,
J = 9.0 Hz, 1H), 8.38 (d, J = 5.7 Hz, 1H); 19F NMR (282 MHz, CDCl3)
d = ꢁ142.0 (m, 2F), ꢁ152.3 (dt, J = 3.1 Hz, J = 20.6 Hz, 1F), ꢁ161.4
(m, 2F); 13C NMR (75 MHz, CD3OD) d = 11.0, 37.6, 39.9, 47.3, 51.1,
51.8, 98.4, 98.5, 111.0 (m), 116.7, 121.6, 124.8, 126.5, 126.6,
135.1, 136.9 (m, JC-F = 930.6 Hz), 141.6 (m, JC-F = 958.8 Hz), 143.4
(m, JC-F = 958.8 Hz), 147.6, 150.3, 150.7, 157.8.
4.2.1.59. N-[2-{(N0-2-(7-chloro-4-quinolyl)aminoethyl-N00-ethyl}-
aminoethyl]heptafluorobutanamide, 53. Using 0.047 g (0.16
mmol) of N-(7-chloro-4-quinolyl)-N0-ethyl-N0-(2-aminoethyl)-1,2-
diaminoethane 10 and perfluorobutyryl chloride (0.02 mL, 0.13
mmol) in the procedure described above and purification by flash
chromatography with MeOH:EtOAc (1:24 v/v) gave 0.027 g
(0.055 mmol, 42% yield) of a light yellow oil. 1H NMR (300 MHz,
CD3OD) d = 1.06 (t, J = 7.2 Hz, 3H), 2.61–2.75 (m, 4H), 2.85 (t,
J = 6.6 Hz, 2H), 3.39–3.49 (m, 4H), 6.56 (d, J = 5.7 Hz, 1H), 7.38
(dd, J = 2.1 Hz, J = 9.0 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), 8.09 (d,
J = 9.0 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H); 19F NMR (282 MHz, CDCl3)
d = –82.6 (t, J = 9.0 Hz, 3F), ꢁ122.1 (q, J = 9.0 Hz, 2F), ꢁ128.7 (s,
2F); 13C NMR (75 MHz, CD3OD) d = 12.1, 39.0, 41.8, 48.8, 52.7,
53.5, 99.7, 99.8, 105.2–117.8 (m), 118.7, 120.8 (t, JC-F = 141.0 Hz),
124.2, 126.0, 127.5, 127.4, 136.4, 149.5, 152.3, 152.3, 152.6, 159.3
(t, JC-F = 94.0 Hz).
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aminoethyl]pentadecafluorooctanamide, 54. Employing 0.051 g
(0.17 mmol)
of
N-(7-chloro-4-quinolyl)-N0-ethyl-N0-(2-amino-
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ride (0.04 mL, 0.17 mmol) in the procedure described above and
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v) gave 0.019 g (0.027 mmol, 16% yield) of a light yellow oil. 1H
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4H), 2.87 (t, J = 6.6 Hz, 2H), 3.45 (q, J = 6.6 Hz, 1H), 6.59 (d,
J = 6.0 Hz, 1H), 7.39 (dd, J = 2.4 Hz, J = 9.0 Hz, 1H), 7.79 (d,
J = 2.4 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 8.37 (d, J = 5.7 Hz, 1H); 19F
NMR (282 MHz, CDCl3) d = ꢁ82.7 (tt, J = 2.3 Hz, J = 9.9 Hz, 3F),
ꢁ121.0 (t, J = 13.0 Hz, 2F), ꢁ122.9 (m, 2F), ꢁ123.4 (m, 2F),
ꢁ123.9 (m, 2F), ꢁ124.1 (m, 2F), ꢁ127.6 (m, 2F); 13C NMR
(75 MHz, CD3OD) d = 12.1, 39.0, 41.9, 52.6, 53.5, 99.7, 118.6,
124.3, 126.1, 127.1, 136.6, 149.0, 151.9, 152.9.
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Acknowledgment
We thank the NIH (Grant RO1AI060792) for financial support.
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