Organocatalyzed highly atom economic one pot synthesis of tetrahydropyridines as antimalarials

Article abstract of DOI:10.1016/j.bmc.2008.11.062

A highly atom economic one pot synthesis of tetrahydropyridines was achieved by l-proline/TFA catalysed multicomponent reaction of β-keto-esters, aromatic aldehydes and anilines. The synthesized compounds were screened against Plasmodium falciparum in vitro and one of them showed antimalarial activity with MIC as low as 0.09 μg/mL.

Full text of DOI:10.1016/j.bmc.2008.11.062

Bioorganic & Medicinal Chemistry 17 (2009) 625–633
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Organocatalyzed highly atom economic one pot synthesis
of tetrahydropyridines as antimalarials
Mridul Misra a, Swaroop Kumar Pandey b, Vivek Parashar Pandey a, Jyoti Pandey a,
Renu Tripathi b, Rama Pati Tripathi a,
*
a Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow, UP 226001, India
b Parasitology Division, Central Drug Research Institute, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly atom economic one pot synthesis of tetrahydropyridines was achieved by L-proline/TFA cata-
Received 3 September 2008
Revised 24 November 2008
Accepted 25 November 2008
Available online 3 December 2008
lysed multicomponent reaction of b-keto-esters, aromatic aldehydes and anilines. The synthesized com-
pounds were screened against Plasmodium falciparum in vitro and one of them showed antimalarial
activity with MIC as low as 0.09 lg/mL.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydropyridines
Antimalarial activity
L
-Proline
Organocatalysis
Schizont maturation
Trifluoroacetic acid
1. Introduction
Owing to their importance in bioorganic and medicinal chemistry,
several methods including the stereocontrolled syntheses were
developed and most of them are associated with many limita-
tions.9,10 Aza Diels-Alder reaction and several of its modifications
has extensively been used to synthesize nitrogen-containing six-
membered ring compounds.11 Towards this endeavor Bruce Pégot
et al. have recently developed an elegant diastereoselective synthe-
sis of 2-substituted-2,3-dihydro-4-pyridone derivatives using chiral
ionic liquids.12 Clarke et al.13 have also reported an InCl3 catalyzed
multicomponent synthesis of polysubstituted 1,2,5,6-tetrahydro-
pyridines in moderate to good yields. Organocatalysis, in general,
provides the avenues towards green chemistry replacing toxic metal
catalysts with degradable organic compounds as catalyst. It has sev-
eral advantages in developing methods to access compounds in an
environment friendly way. On the other hand, the atom economic
synthesis14 offers the most economical method of preparing organic
compounds with no loss of the starting material and therefore eco-
friendly. Moreover, application of metal catalyst in the synthesis of
biologically active compounds is sometimes unwanted as the pres-
ence of even minute amount of residual metal would lead to serious
consequences. In view of the above, we were interested to develop a
nonmetallic, organocatalytic, atom economic method for the syn-
theses of tetrahydropyridines and evaluate them for different bio-
logical activities. In the first instance, the synthesized compounds
were evaluated against Plasmodium falciparum for their antimalarial
activity.
Malaria is one of the most important infectious diseases claiming
more than 2.7 million deaths and infecting up to 900 million people
worldwide each year.1–3 Currently, there are several drugs known
for the treatment of this disease but only limited ones are safe drugs.
The recent reports of emerging resistance against existing drugs3,4
has resulted in great efforts on research and development activities
from academic institutes rather than pharmaceutical industries be-
cause of limited commercial opportunities. The piperidine subunit is
a prominent pharmacophore, occurring in the variety of biologically
important synthetic and natural products.5 This subunit has great
chemotherapeutic values as numerous lead molecules with promi-
nent biological activities are clinical candidates for several dis-
eases.5e Tetrahydropyridine (THP) derivatives are also useful
against several metabolic disorders and human ailments. The prom-
inent biological activities associated with this pharmacophore are
antiparasitic, antimicrobial, anticancer, antiviral etc. Further, these
are intricately involved in MAO based mechanism in Parkinson’s dis-
ease6 and as inhibitors of farnesyl transferase7 and dihydroorate
dehydrogenase8 and also play key roles in many disease processes.
* Corresponding author. Tel.: +91 0522 2612411; fax: +91 522 2623405/
2623938/2629504.
E-mail address: rpt.cdri@gmail.com (R.P. Tripathi).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.11.062

626
M. Misra et al. / Bioorg. Med. Chem. 17 (2009) 625–633
Our method consists of the reaction of aromatic aldehydes, ani-
lines, and a b-keto ester under the influence of -proline/TFA as
organocatalyst. The choice of -proline as organocatalyst is based
tons of carbethoxy group were observed as triplet at around d
L
1.42–1.54 ppm, respectively. It is appropriate to mention here that
sometimes the quartet pertaining to the methylene protons of car-
bethoxy substituents appeared with two different chemical shifts
due to diastereoisomeric nature of the products. In the 13C NMR
spectrum, the C-5 carbon of the above tetrahydropyridines (1–
22) was observed at around d 34.0–37.6 ppm while the C-2 carbon
was appeared at around d 53.0–59.4 ppm. The C-6 and C-3 carbons
were observed at around d 54.2–61.8 and d 96.9–102.3 ppm, respec-
tively. The aromatic carbons (ArCH) were appeared at around d
113.4–132.3 ppm while the C-4 and quaternary aromatic carbon
were observed in the range of d 120.7–164.4 ppm. The quaternary
carbon of carbethoxy and carbmethoxy group were observed at
around d 168.4–172.0 ppm The methyl carbon of carbmethoxy
group appeared at around d 51.0 ppm, while the methylene and
methyl carbons of carbethoxy group appeared at around d 60.0–
64.3 and d 15.2–19.1 ppm, respectively.
L
on the facts that it acts as an excellent Lewis acid–base catalyst
in a variety of organic reactions.15
2. Results and discussion
2.1. Chemistry
The compounds (1–21) were synthesized by reacting b-keto es-
ters (1.0 equiv.), aromatic aldehydes, and anilines (2.0 equivalents
each) in acetonitrile in the presence of L-proline and TFA (20 mol%
each) at ambient temperature (Scheme 1).
At first, aniline, 4-methoxy benzaldehyde, and methyl acetoac-
etate were selected as the model substrates and reacted under
different experimental variants (Table 1). We have compared
As evident from Table 2 the aromatic aldehydes with nitro- and
benzyloxy substituents did offer only moderate yield of the prod-
uct, however, other aldehydes gave good yields of the required tet-
rahydropyridines irrespective of the substituents in benzene ring
of the aldehyde. Further, 4-methoxy aniline resulted in better
yields of the required tetrahydropyridines compared to either 4-
chloro- and 4-bromo aniline.
L
-proline/TFA with other catalysts including InCl3, silica-sulfuric
acid (SSA), ortho-phosphoric acid, perchloric acid, and TFA alone
to set up standard reaction conditions. The effect of -proline alone
L
and in combination with TFA, using varying amount of this cata-
lyst-combination in various organic solvents as well as in water
were also studied. Among all the experimental variants the reac-
tion with 20 mol% of L-proline and TFA in CH3CN at ambient tem-
The most probable reaction mechanism (Fig. 1) involves the ini-
tial formation of an imine A and a Knoevenagel product C formed
through proline catalysed enamine B mediated reaction. Mannich
like reaction of aniline with Knoevenagel adducts C results an
intermediate enamine D which undergo Aza Diels-Alder cycliza-
tion with imine A and results the required tetrahydropyridine E.
The proposed reaction mechanism is supported by the fact that
Knoevenagel adduct (23) and imine (24) have been isolated during
one of such representative reaction of 4-methoxybenzaldehdye,
methyl acetoacetate and aniline as shown in Scheme 2.
The relative stereochemistry in the above compound with 2-
and 6-substituents being trans- to each other was based on the
extensive 1H NMR experiments involving NOESY and NOE experi-
ments. Absence of any NOE between H-2 and H-6 of tetrahydro-
pyridine indicates that they are trans to each other, Figure 2.
Further, the 1H NMR and 13C NMR spectra of our compounds were
identical to those reported earlier by Clarke et al.13
perature (Table 1, entry 10) gave the best result with 72% yield of
the required 1,2,6-triphenyl-4-phenylamino-1,2,5,6-tetrahydro-
pyridine-3-carboxylic acid methyl ester (1).
The structure of these compounds was established on the basis
of their spectroscopic data and microanalysis. The IR spectrum of
the compounds, in general, exhibited the absorption band at
around 1656–1593 cmÀ1 indicating that the carbonyl group of
carbmethoxy or carbethoxy substituents and olefinic bonds are
in conjugation. The ESMS (mass spectra) of the compounds showed
their respective [M+H]+ peaks. In the 1H NMR spectrum, the proton
at C-2 in the above tetrahydropyridines (1–22) was observed either
as singlet at around d 6.18–6.36 ppm or it appeared along with the
multiplets of aromatic protons ranging from d 6.70 to 6.19 ppm.
The H-6 in the above compounds was apparent as broad singlet
at around d 5.00 ppm. The two methylene protons of H-5a and
H-5b were appeared as two distinct dd [at around d 2.62–
2.76 ppm with coupling constant in the range of 5.0 (J1) and
15.0 Hz (J2) and at d 2.73–2.91 ppm with coupling constant in the
range of 2.0 (J1) and 15.0 Hz (J2), respectively] or as doublet [at
around d 2.91 ppm with coupling constant in the range of 5.0
(J)]. The aromatic protons pertaining to the phenyl substituent at
C-2 and C-6 and anilinyl moiety at C-4 were observed as mixture
of singlets, doublets and multiplets at around d 6.26–8.64 ppm.
The only exchangeable secondary amine proton (NH) attached at
C-4 appeared as br s at around d 10.20 ppm. The methyl protons
of carbmethoxy group appeared as singlet at around d 3.95 ppm,
while the methylene protons of carbethoxy group appeared as
quartets or multiplet at around d 4.23–4.51 ppm and methyl pro-
2.2. Biology
2.2.1. Results and discussion
The above compounds 1–21 were assayed for their blood schiz-
ontocidal activity against P. falciparum 3D7 strain as per earlier re-
ported protocols.16–18 Initially these compounds were tested at
10.0, 5.0, 2.5, and 1.25
8, 9, 10, 11, 12, 13, 15, 16, 18, 20, and 21 displayed 100% schizont
inhibition at 10 g/mL, while compounds 2, 11, 17 displayed
lg/mL concn. Compounds 1, 3, 4, 5, 6, 7,
l
only 33%, 23%, and 83% schizont inhibition at 10 lg/mL (Table 3).
NH2
R1
NH
N
O
O
R1
O
L-proline/TFA, 20 mol%
+
OR
H3C
OR
CHO
AcCN/ 20 - 30 ºC
16-24 h
R2
R2
R2
R1
1-22
Scheme 1. Synthesis of tetrahydropyridines from different aromatic aldehydes, anilines, and b-keto esters.

M. Misra et al. / Bioorg. Med. Chem. 17 (2009) 625–633
627
Table 1
dines with unsubstituted N-phenyl moiety. In contrast to these re-
sults, the incorporation of chloro- and bromo-substituents at the
4-position of the N-phenyl substituent (compounds 2, 8, and 9) re-
sulted in loss of activity as compared to compounds 1 and 5 with
unsubstituted N-phenyl moiety. The introduction of a benzyloxy
substituent at the 4-position of the 2- and 6-phenyl substituents
(compound 11) resulted in loss of antimalarial potency as com-
pared to compound 1. While tetrahydropyridines with thiophenyl
and pyridyl groups (compounds 15, 16, and 20) as 2- and 6-substit-
uents resulted in enhancement in schizontocidal activity. Further,
replacement of carbmethoxy substituent with carbethoxy group
as ester moiety at C-3 in tetrahydropyridines (compounds 14, 15,
16, 17, 18, 19, and 20) resulted in slight decrease in the blood
schizontocidal activity indicating that ester group with smaller al-
kyl moiety is preferable over larger one.
Optimization experiments during reaction of 4-methoxy benzaldehyde, aniline, and
methyl acetoacetate
Entry
Catalyst
Solvent
Reaction
time
% Yields
1
2
3
4
InCl3
CH3CN
CH3CN
CH3CN
CH3CN
50
36
24
24
25
10
5
Silica sulfuric acid
ortho-Phosphoric acid
DBU
Undesired
productsa
Undesired
products
Undesired
productsa
45
50
72
72
30
5
6
Glycosylamino acid
CH3CN
CH3CN
24
24
L
-Proline
7
8
9
10
11
12
13
14
L
L
L
L
L
L
L
L
-Proline + TFA (5 mol% each)
-Proline + TFA (10 mol% each)
-Proline + TFA (40 mol% each)
-Proline + TFA (20 mol% each)
-Proline + TFA (20 mol% each)
-Proline + TFA (20 mol% each)
-Proline + TFA (20 mol% each)
-Proline + TFA (20 mol% each)
CH3CN
CH3CN
CH3CN
CH3CN
THF
DMF
DMSO
H2O
24
24
21
21
24
24
24
24
3. Conclusion
45
40
10
We have developed a metal free, highly atom economic organ-
ocatalytic multicomponent synthesis of tetrahydropyridines in
moderate to good yields. The compounds have great potential in
development of new chemotherapeutics. In the first instance, these
compounds displayed antimalarial activity and their biopotential is
being investigated in great detail.
a
Among the undesired product the major product was found to be Schiff’s base
of aldehyde and aniline.
Compounds 1, 3, 4, 8, 12, 16, 18, and 20 exhibited 100% schizontocid-
al activity at 1.25
for their minimum inhibitory concentration (MIC) at lower dilutions
rangingfrom0.78to 0.05 g/mL. Theonlycompound4 showed100%
inhibition at 0.09 g/mL concn, while the compounds 3, 16, and 20
showed the 100% schizont inhibition at 0.39 g/mL concentrations.
However, the compounds 1, 8, 12, and 18 exhibited slight inhibition
at 0.39 g/mL concentrations (Table 4).
The effects of various substituents in the phenyl group attached
to ring carbons and C-4 nitrogen atom in tetrahydropyridines was
examined in order to find out the structure–activity relationship in
this series of compounds. As evident from Table 3, the introduction
of fluoro- and bromo-substituents at the 4-position and chloro- at
the 3-position on to the 2- and 6- phenyl substituents of tetrahy-
dropyridines (compounds 3, 5, 13) did not alter the schizontocidal
potential whereas the only compound (3) exhibited a moderate
enhancement in antimalarial efficacy as compared to compound
1. However, introduction of p-methoxy group in the N-phenyl
group (compounds 7, 4, 21, and 6) resulted in marked increase in
blood schizontocidal activity as compared to the tetrahydropyri-
lg/mL. These compounds were further screened
l
4. Experimental
4.1. Chemistry
l
l
l
Commercially available reagent grade chemicals were used as
received. All reactions were followed by TLC on E. Merck Kieselgel
60 F254, with detection by UV light and/or spraying a 20% KMnO4
aq soln. Column chromatography was performed on silica gel
(230–400 mesh, E. Merck). IR spectra were recorded as thin films
or in chloroform soln with a Perkin–Elmer Spectrum RX-1 (4000–
450 cmÀ1) spectrophotometer. 1H and 13C NMR spectra were re-
corded on a Brucker DRX-300 in CDCl3. Chemical shift values are
reported in ppm relative to SiMe4 as internal reference, unless
otherwise stated; s (singlet), d (doublet), t (triplet), m (multiplet);
J in hertz. FAB mass spectra were performed using a mass Spec-
trometer Jeol SX-102 and ESI mass spectra with Quattro II (Micro-
mass). Melting points were obtained manually by capillary
Table 2
Synthesis of tetrahydropyridines with different aromatic aldehydes, anilines, and b-keto ester
Entry
Aldehyde
Aniline
b-Keto compound
Product
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4-Methoxybenzaldehyde
4-Bromobenzaledehyde
4-Fluorobenzaldehyde
4-Fluorobenzaldehyde
4-Bromobenzaldehyde
3-Chlorobenzaldehyde
4-Methoxybenzaldehyde
4-Methoxybenzaldehyde
4-Methoxybenzaldehyde
4-Fluorobenzaldehyde
4-Benzyloxybenzaldehyde
Benzaldehyde
3-Chlorobenzaldehyde
3-Chlorobenzaldehyde
Thiophene-2-carboxaldehyde
Thiophene-2-carboxaldehyde
3-Chlorobenzaldehyde
Benzaldehyde
Aniline
4-Chloroaniline
Aniline
p-Anisidine
Aniline
p-Anisidine
p-Anisidine
4-Chloroaniline
4-Bromoaniline
4-Chloroaniline
Aniline
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Methyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Ethyl acetoacetate
Methyl acetoacetate
Methyl acetoacetate
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
18
18
24
18
20
18
19
20
24
21
16
17
16
22
21
22
24
18
22
20
22
28
70
70
65
60
65
60
75
70
65
65
55
70
60
70
65
60
65
60
75
55
65
70
Aniline
Aniline
p-Anisidine
4-Chloroaniline
p-Anisidine
4-Chloroaniline
p-Anisidine
4-Chloroaniline
Aniline
Benzaldehyde
Pyridine-3-carboxaldehyde
4-Bromobenzaldehyde
3-Nitrobenzaldehyde
p-Anisidine
Aniline

628
M. Misra et al. / Bioorg. Med. Chem. 17 (2009) 625–633
H
H
O
N
+
NH2
A
O
O
O
HOOC
+
O
N
H
HN
OR
O
OR
B
O
O
O
O
NH 2
H3C
N
N
O
H
H
O
O
O
H3O+
H3C
H3C
-H2O
H
OR
OR
OR
C
O
NH
N
O
NH
N
O
NH O
OR
H2C
H3C
OR
OR
D
E
Figure 1. Proposed reaction mechanism for the formation of tetrahydropyridines.
NH2
CHO
NH
N
O
O
O
O
L-proline/TFA, 20 mol%
O
OCH3
OCH3
+
H3C
OMe
+
N
H3C
OCH3
AcCN/ 20 - 30 ºC
8 h
+
OCH3
24 (10%)
OCH3
OCH3
23 (10%)
OCH3
13
(20%)
Scheme 2. Synthesis of tetrahydropyridine (13) and reaction intermediates after 8 h.
4.1.1. General procedure for the preparation of compounds 1–22
To a magnetically stirred solution of b-keto ester (8.0 mmol),
aromatic aldehyde (14.4 mmol), and aniline (15.6 mmol) in aceto-
NH
nitrile (25.0 mL), L-proline (1.5 mmol), and trifluoroacetic acid
O
4.94%
0%
H
(1.09 mmol) were added and the reaction mixture was stirred at
ambient temperature. The stirring continued till the disappearance
of aldehyde, the reaction mixture was filtered and the solid so ob-
tained was washed with aqueous HCl (10%) followed by water and
n-hexane sequentially to give colourless powder which was dried
under vacuum. For elemental analyses the compound was filtered
through a short column of SiO2. However, if no precipitate appears
during reaction, the reaction mixture was evaporated under re-
duced pressure and extracted with ethyl acetate. The organic layer
was washed with aqueous HCl (10%) followed by water and dried
(anhydrous Na2SO4), evaporated under reduced pressure to give a
crude mass. The latter was purified by column chromatography
17.49%
OCH3
H
H
H
N
9.12%
H
H3CO
OCH3
Figure 2. NOE percentage between H-2, H-6, and aromatic protons f or compound 1.
methods and are uncorrected. Elemental analyses were performed
on a Perkin–Elmer 2400 II elemental analyzer.

M. Misra et al. / Bioorg. Med. Chem. 17 (2009) 625–633
629
Table 3
C
33H32N2O4: Calcd C, 76.13; H, 6.20; N, 5.38. Found: C, 76.14;
Antimalarial activity of tetrahydropyridines against P. falciparum 3D7
H, 6.19; N, 5.37.
Entry Compound
% Inhibition of Schizonts of P. falciparum at different
concentrations
4.1.3. Methyl 2,6-bis(4-bromophenyl)-1-(4-chlorophenyl)-4-(4-
chlorophenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
(2)
10
lg/mL
5
l
g/mL
2.5
lg/mL
1.25 lg/mL
1
2
1
2
100
33
100
00
100
00
100
100
85
100
90
100
91
100
02
100
81
50
93
100
00
100
100
46
33
86
100
25
93
00
100
46
16
86
White solid, mp 160–163 °C; Rf = 0.5 (ethyl acetate/hexane =
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
100
100
100
100
100
100
100
100
23
100
100
100
100
100
83
100
100
100
100
100
100
100
100
02
100
81
92
100
100
66
1/4); FTIR (KBr):
t 3741, 3618, 3020, 2360, 1652, 1614, 1497,
1216 cmÀ1 1H NMR (300 MHz, CDCl3 + CCl4): d 2.68 (dd, J = 15.0
;
and 1.95 Hz, 1H, H-5a), 2.81 (dd, J = 15.2 and 5.6 Hz, 1H, H-5b),
3.95 (s, 3H, OMe), 5.05 (br s, 1H, H-6), 6.26–6.37 (m, 5H, 4ArH,
and H-2), 6.98–7.03 (m, 4H, ArH) , 7.11–7.28 (m, 4H, ArH), 7.39–
7.44 (m, 4H, ArH), 10.23 (br s, 1H, NH) ppm; 13C NMR (50 Hz,
CDCl3 + CCl4): d 33.9 (CH2, C-5), 51.7 (C, COOCH3), 55.3 (CH, C-2),
57.9 (CH, C-6), 98.3 (C, C-3), 114.4 (ArCH), 121.0, 121.7, and
122.5 (3ArC), 127.3, 128.4, 128.6, 129.4, 129.6, 131.9, 132.3 (ArCH),
132.5, 136.5, 141.2, 142.4, 145.2, 155.6 (8ArC and C-4), 168.4 (CO);
ESMS (m/z): [M+H]+, 663. Elemental analysis for C31H24Br2Cl2N2O2:
Calcd C, 67.23; H, 5.13; N, 4.75. Found: C, 67.24; H, 5.12; N, 4.77.
100
00
100
00
100
100
100
100
100
100
100
100
100
100
92
100
95
100
25
100
33
4.1.4. Methyl 2,6-bis(4-fluorophenyl)-1-phenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (3)
White solid, mp 160 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
Chloroquinea 100
97
86
FTIR (KBr):
t
3738, 3681, 3621, 3020, 1652, 1652, 1595, 1504,
23
Control
38% Schizonts development
1372, 1323, 1216 cmÀ1
;
1H NMR (300 MHz, CDCl3 + CCl4): d 2.78
a
The concentration used are 100, 50, 25, and 12.5 ng/mL.
(dd, J = 14.9 and 1.56 Hz, 1H, H-5a), 2.87 (dd, J = 15.1 and 5.3 Hz,
1H, H-5b), 3.97 (s, 3H, OMe), 5.10 (br s, 1H, H-6), 6.40–6.51 (m,
5H, 4ArH, and H-2), 6.63–6.68 (t, J = 7.1 Hz, 1H, ArH), 6.85–7.26
(m, 13H, ArH), 10.32 (br s, 1H, NH) ppm; 13C NMR (50 MHz,
CDCl3 + CCl4): d 34.2 (CH2, C-5), 51.5 (C, COOCH3), 55.0 (CH, C-2),
57.7 (CH, C-6), 98.2 (C, C-3), 113.4, 115.3, 115.7, 116.1, 117.1,
126.2, 126.4, 128.2, 128.4, 128.5, 128.6, 129.4, 129.5, 129.8 (ArCH),
138.1, 138.5, 139.7, 146.9, 156.4, 159.5, 164.4 (6ArC and C-4),
168.6 (CO); ESMS (m/z): [M+H]+, 496.
Table 4
In vitro antimalarial activity of selected compounds (0.78–0.05 lg/mL) against P.
falciparum 3D7
Entry Compound
% Inhibition of Schizonts at different concentrations (
lg/mL)
of test compounds
0.78
0.39
0.19
0.09
0.05
1
2
3
4
5
6
7
8
9
1
3
4
94
100
100
95
96
100
66
67
100
100
75
90
100
33
47
75
100
41
33
75
00
97
97
45
33
100
33
00
25
00
42
86
25
16
91
16
00
16
00
42
54
4.1.5. Methyl 2,6-bis(4-fluorophenyl)-1-(4-methoxyphenyl)-4-
(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (4)
8
12
16
18
20
White solid, mp 205 °C, Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
t
3677, 3416, 3062, 2362, 1654, 1607, 1510, 1456,
1243 cmÀ1
;
1H NMR (300 MHz, CDCl3 + CCl4): d 2.62 (dd, J = 15.2
100
100
100
Chloroquine* 100
and 2.6 Hz, 1H, H-5a), 2.73 (dd, J = 15.2 and 5.3 Hz, 1H, H-5b),
3.68 (s, 3H, ArOMe), 3.77 (s, 3H, ArOMe), 3.96 (s, 3H, OMe), 4.97
(br s, 1H, H-6), 6.19 (s, 1CH, H-2), 6.35–6.38 (m, 4H, ArH), 6.61–
6.68 (m, 4H, ArH) 6.92–7.01 (m, 4H, ArH), 7.09–7.14 (m, 2H,
ArH), 7.19–7.24 (m, 2H, ArH), 10.18 (br s, 1H, NH) ppm; 13C NMR
(50 MHz, CDCl3 + CCl4): d 34.1 (CH2, C-5), 51.3 (C, COOCH3), 55.6
(CH, C-2), 55.6 (ArOCH3), 55.8 (ArOCH3), 57.6 (CH, C-6), 97.1 (C,
C-3), 114.5, 114.9, 115.1, 115.5, 115.6, 116.0, 128.1, 128.4, 128.6,
128.1 (ArCH), 130.9, 139.0, 140.0, 141.5, 151.8, 157.1, 158.3,
159.5, 164.4 (8ArC and C-4), 168.4 (CO); ESMS (m/z): [M+H]+, 530.
10
Control
46% Schizonts development
*
The concentration used are 100, 50, 25, 12.5, and 6.25 ng/mL.
over SiO2 (60–120 mesh) in EtOAc: n-hexane (40:60) as eluent to
give the desired tetrahydropyrdines 1–22.
4.1.2. Methyl 2,6-bis(4-methoxyphenyl)-1-phenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (1)
White solid, mp 180 °C; Rf = 0.5 (ethylacetate/hexane = 1/4);
FTIR (KBr):
1251 cmÀ1
t
3426, 2922, 2369, 1656, 1597, 1504, 1442,
4.1.6. Methyl 2,6-bis(4-bromophenyl)-1-phenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (5)
;
1H NMR (300 MHz, CDCl3 + CCl4):
d
2.76 (dd,
J = 14.8 and 1.9 Hz, 1H, H-5a), 2.87 (dd, J = 14.9 and 5.4 Hz, 1H,
H-5b), 3.80 (s, 3H, ArOMe), 3.82 (s, 3H, ArOMe), 3.95 (s, 3H,
OMe), 5.10 (br s, 1H, H-6), 6.37–6.39 (m, 3H, 2ArH, and H-2),
6.51–6.54 (d, J = 8.3 Hz, 2H, ArH), 6.58–6.63 (t, J = 7.1 Hz, 1H,
ArH), 6.73–6.84 (m, 4H, ArH), 7.05–7.33 (m, 9H, ArH), 10.31
(br s, 1H, NH) ppm; 13C NMR (50 MHz, CDCl3 + CCl4): d 34.1
(CH2, C-5), 51.3 (C, COOCH3), 54.9 (CH, C-2), 55.4 (ArOCH3),
55.5 (ArOCH3), 57.9 (CH, C-6), 98.7 (C, C-3), 113.4, 113.9,
114.4, 116.6, 126.0, 126.2, 127.8, 128.1, 129.3, 129.7 (ArCH),
135.0, 136.2, 138.4, 147.4, 156.6, 158.5, 159.1 (6ArC and C-4),
168.8 (CO); ESMS (m/z): [M+H]+, 519.2. Elemental analysis for
White solid, mp 140 °C; Rf = 0.5 (ethyl acetate/hexane = 1/4);
FTIR (KBr):
1216, cmÀ1
t
3685, 3395, 3020, 2361, 1653, 1595, 1500, 1427,
;
1H NMR (300 MHz, CDCl3 + CCl4): d 2.77 (dd, J = 15.0
and 2.25 Hz, 1H, H-5a), 2.86 (dd, J = 15.0 and 5.31 Hz, 1H, H-5b),
3.96 (s, 3H, OMe), 5.06 (br s, 1H, H-6), 6.38–6.70 (m, 5H, 4ArH,
and H-2), 6.76–6.85 (m, 1H, ArH), 7.02–7.55 (m, 9H, ArH), 7.69–
7.71 (d, J = 6.99 Hz, 4H, ArH), 10.29 (br s, 1H, NH) ppm; 13C NMR
(50 Hz, CDCl3 + CCl4): d 34.0 (CH2, C-5), 51.6 (OCH3), 55.2 (CH, C-
2), 57.8 (CH, C-6), 97.9 (C, C-3), 113.3, 117.2 (ArCH), 120.7, 121.4
(ArC and C-4) 126.2, 126.5, 128.5, 128.9, 129.5, 131.8, 132.1
(ArCH), 138.0, 141.9, 143.3, 146.9, 156.4 (ArC), 168.7 (CO); ESMS

630
M. Misra et al. / Bioorg. Med. Chem. 17 (2009) 625–633
(m/z): [M+H]+, 622. Elemental analysis for C31H26N2O2 Br2: Calcd C,
60.21; H, 4.24; N, 4.53. Found: C, 60.22; H, 4.23; N, 4.52.
3.78 (s, 3H, ArOMe) 3.81 (s, 3H, ArOMe), 3.96 (s, 3H, OMe), 5.04
(br s, 1H, H-6), 6.26–6.29 (m, 3H, ArH, and H-2), 6.42 (d,
J = 8.1 Hz, 2H, ArH), 6.80–6.85 (m, 4H, ArH), 6.98–7.17 (m, 8H,
ArH), 10.28 (br s, 1H, NH) ppm; 13C NMR (50Hz, CDCl3 + CCl4): d
34.0 (CH2, C-5), 51.6 (OCH3), 55.1 (CH, C-2), 57.8 (CH, C-6), 61.2
(2ArOCH3), 114.4, 115.4, 115.8, 116.3, 116.5 (ArCH), 122.4 (ArC),
127.2, 128.1, 128.3, 128.4, 128.8, 129.3, 129.5, 129.9 (ArCH),
132.1, 136.6, 137.8, 138.9, 145.3, 155.5, 159.6 (ArC), 164.5 (ArC),
168.2 (CO); ESMS (m/z): [M+H]+, 562. Elemental analysis for
C33H30N2O4Br2: Calcd C, 58.42 ; H, 4.46; N, 4.13. Found: C, 58.51;
H, 4.48; N, 4.11.
4.1.7. Methyl 2,6-bis(3-chlorophenyl)-1-(4-methoxyphenyl)-4-
(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (6)
White solid, mp 160 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
t
3781, 3374, 3019, 2361, 1652, 1594, 1511, 1465,
;
1371, 1216 cmÀ1
1H NMR (300 MHz, CDCl3 + CCl4): d 2.64 (dd,
J = 15.0 and 2.37 Hz, 1H, H-5a), 2.75 (dd, J = 15.2 and 5.4 Hz, 1H,
H-5b), 3.68 (s, 3H, ArOMe), 3.77 (s, 3H, ArOMe), 3.91 (s, 3H,
OMe), 4.97 (br s, 1H, H-6), 6.19–6.38 (m, 5H, 4ArH, and H-2),
6.61–6.68 (m, 4H, ArH), 6.92–7.24 (m, 8H, ArH), 10.18 (br s, 1H,
NH) ppm; 13C NMR (50 Hz, CDCl3 + CCl4): d 33.4 (CH2, C-5), 50.9
(OCH3), 55.1 (CH, C-2), 55.2 (ArOCH3), 55.7 (ArOCH3), 57.5 (CH,
C-6), 114.0, 114.4, 114.7, 124.8, 124.9, 126.6, 126.9, 127.3, 128.0,
129.8, 130.0 (ArCH), 134.3, 134.5, 140.6, 145.2, 146.4, 151.6,
156.4, 158.1 (ArC and C-4), 167.9 (CO); ESMS (m/z): [M+H]+, 562.
Elemental analysis for C33H30N2O4Cl2: Calcd C,67.23 ; H, 5.13 ; N,
4.75. Found: C, 67.24; H, 5.12; N, 4.76.
4.1.11. Methyl-(4-chlorophenyl)-4-(4-chlorophenylamino)-2,6-
bis(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
(10)
White solid, mp 176 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
;
t 3697, 3627, 3021, 2360, 1655, 1600, 1499, 1216 cm
À1
1H NMR (300 MHz, CDCl3 + CCl4): d 2.70 (dd, J = 14.8 and
1.95 Hz, 1 H, H-5a) , 2.82 (dd, J = 15.0 and 5.3 Hz, 1H, H-5b), 3.96
(s, 3H, OMe), 5.07 (br s, 1H, H-6), 5.94–6.35 (m, 5H, 4ArH, and H-
2), 6.90–7.34 (m, 12H, ArH), 10.29 (br s, 1H, NH) ppm; 13C NMR
(50 Hz, CDCl3 + CCl4): d 34.0 (CH2, C-5), 51.3 (OCH3), 55.5 (CH, C-
2), 57.6 (CH, C-6), 97.1 (C, C-3), 114.4, 114.9, 115.1, 115.5, 115.6,
116.0, 128.1, 128.4, 128.5, 128.6, 128.8 (ArCH), 130.9, 139.0,
139.8, 141.3, 151.9, 156.8, 158.3, 159.4, 164.3 (8ArC and C-4),
168.4 (CO); ESMS (m/z): [M+H]+, 565.
4.1.8. Methyl 1,2,6-tris(4-methoxyphenyl)-4-(4-methoxy-
phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (7)
White solid, mp 158–160 °C; Rf = 0.5 (ethyl acetate/hexane = 1/
5); FTIR (KBr):
t 3678, 3437, 3020, 2360, 1649, 1512, 1461,
1217 cmÀ1 1H NMR (300 MHz, CDCl3 + CCl4): d 2.64 (dd, J = 15.0
;
and 2.4 Hz, 1H, H-5a), 2.77 (dd, J = 15.0 and 5.4 Hz, 1H, H-5b),
3.68 (s, 3H, ArOMe), 3.77 (s, 3H, ArOMe), 3.79 (s, 3H, ArOMe),
3.82 (s, 3H, ArOMe), 3.91 (s, 3H, OMe), 4.98 (br s, 1H, H-6), 6.22
(s, 1CH, H-2), 6.30 (d, J = 7.6 Hz, 2H, ArH), 6.43 (d, J = 9.0 Hz, 2H,
ArH), 6.64 (d, J = 7.8 Hz, 4H, ArH), 6.79–6.84 (m, 4H, ArH,), 7.06
(d, J = 8.5 Hz, 2H, ArH), 7.17 (d, J = 8.5 Hz, 2H, ArH), 10.16 (br s,
1H, NH) ppm; 13C NMR (50 MHz, CDCl3 + CCl4): d 34.1 (CH2, C-5),
51.2 (OCH3), 55.4 (CH, C-2), 55.5 (ArOCH3), 55.6 (ArOCH3), 55.9
(ArOCH3), 57.8 (CH, C-6), 97.5 (C, C-3), 113.8, 113.9, 114.3, 114.3,
114.8, 128.0, 128.2, 128.5 (ArCH), 131.2, 135.5, 136.5, 141.9,
151.4, 157.4, 158.1, 158.4, 159.0 (8ArC and C-4), 168.9 (CO); ESMS
(m/z): [M+H]+, 580. Elemental analysis for C35H36N2O6, 72.39; H,
6.25; N, 4.82. Found: C, 72.36; H, 6.26; N, 4.81.
4.1.12. Methyl 2,6-bis(4-(benzyloxy)phenyl)-1-phenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate (11)
White solid, mp 155 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
t
3654, 3450, 3032, 2363, 1656, 1592, 1504, 1453,
;
1378, 1246 cmÀ1
1H NMR (300 MHz, CDCl3 + CCl4): d 2.74–2.79
(m, 1H, H-5a), 2.84–2.91 (dd, J =15.0 and 5.2 Hz, 1H, H-5b), 3.97
(s, 3H, OMe), 4.99–5.18 (m, 5H, 2 OCH2, H-6), 6.38–6.56 (m, 5H,
4ArH, and H-2), 6.63 (t, J = 7.1Hz , 1H, ArH), 6.90–6.93 (m, 4H,
ArH), 7.09–7.11 (m, 7H, ArH), 7.17–7.28 (m, 2H, ArH), 7.35–7.45
(m, 10H, ArH), 10.31 (br s, 1H, NH) ppm; 13C NMR (50 Hz, CDCl3
+ CCl4): d 34.1 (CH2, C-5), 51.3 (OCH3), 55.0 (CH, C-2), 57.9 (CH,
C-6), 70.3, and 70.4 (OCH2), 98.5 (C, C-3), 113.4, 114.9, 115.4,
116.5, 126.0, 126.2, 127.8, 127.9, 128.1, 128.3, 128.9, 129.2, 129.7
(ArCH), 135.3, 136.4, 137.5, 137.6, 138.3, 147.3, 156.6, 157.8,
158.3 (ArC and C-4), 168.8 (CO); ESMS (m/z): [M+H]+, 672. Elemen-
tal analysis for C45H40N2O4: Calcd C, 67.23; H, 5.13; N, 4.75. Found:
C, 67.24; H, 5.15; N, 4.73.
4.1.9. Methyl-(4-chlorophenyl)-4-(4-chlorophenylamino)-2,6-
bis(methoxyphenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate
(8)
White solid, mp 195 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
t
3400, 3020, 2360, 1652, 1603, 1500, 1432, 1216; 1H
4.1.13. Methyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetra-
hydropyridine-3-carboxylate (12)
NMR (300 MHz, CDCl3): d 2.71 (dd, J = 15.0 and 5.5 Hz, 1H, H-5a),
2.85 (dd, J = 15.0 and 2.1 Hz, 1H, H-5b), 3.80 (s, 3H, ArOMe), 3.82
(s, 3H, ArOMe), 3.95 (s, 3H, OMe), 5.06 (br s, 1H, H-6), 6.26–6.32
(m, 3H, ArH, and H-2), 6.44–6.47 (d, J = 9.0 Hz, 2H, ArH), 6.82–
6.86 (m, 4H, ArH), 7.00–7.20 (m, 8H, ArH), 10.24 (br s, 1H, NH)
ppm; 13C NMR (50 Hz, CDCl3): d 34.0 (CH2, C-5), 51.6 (OCH3),
55.1 (CH, C-2), 55.2 (ArOCH3), 55.5 (ArOCH3), 57.9 (CH, C-6), 97.9
(C, C-3), 113.3, 117.2 (ArCH), 120.7, 121.4 (ArC), 126.2, 126.5,
128.5, 128.8, 129.5 (ArCH), 131.8, 132.1, 138.0, 141.8, 143.3,
146.8, 156.4 (ArC and C-4), 168.7 (CO); ESMS (m/z): [M+H]+, 588.
Elemental analysis for C33H30N2O4Cl2: Calcd C, 67.23; H, 5.13; N,
4.75. Found: C, 67.25; H, 5.11; N, 4.78.
White solid, mp 194 °C; Rf = 0.5 (ethyl acetate/hexane = 1/4);
FTIR (KBr):
;
t 3859, 3427, 3020, 2360, 1653, 1592, 1498, 1257 cm
À1
1H NMR (300 MHz, CDCl3 + CCl4): d 2.73 (dd, J = 15.0 and
2.2 Hz, 1H, H-5a), 2.85 (dd, J = 15.0 and 5.4 Hz, 1H, H-5b), 3.91 (s,
3H, OMe), 5.1 (br s, 1H, H-6), 6.25–6.28 (m, 2H, ArH, and H-2),
6.42–6.50 (m, 2H, ArH), 6.54–6.59 (t, J = 7.2 Hz, 1H, ArH), 6.99–
7.09 (m, 5H, ArH), 7.13–7.29 (m, 10H, ArH), 10.29 (br s, 1H, NH)
ppm; 13C NMR (50 Hz, CDCl3 + CCl4): d 34.0 (CH2, C-5), 51.4
(OCH3), 55.5 (CH, C-2), 58.7 (CH, C-6), 98.5 (C, C-3), 113.4, 116.7,
126.1, 126.2, 126.8, 127.0, 127.6, 128.7, 129.0, 129.2, 129.3, 129.7
(ArCH), 138.3, 143.2, 144.3, 147.3, 156.5 (4ArC and C-4), 168.9
(CO); ESMS (m/z): [M+H]+, 460. Elemental analysis for
C31H28N2O2: C, 80.84; H, 6.13; N, 6.08. Found: C, 80.82; H, 6.15;
N, 6.06.
4.1.10. Methyl-1-(4-bromophenyl)-4-(4-bromophenylamino)-
2,6-bis(4-methoxyphenyl)-1,2,5,6-trahydropyridine-3-
carboxylate (9)
White solid, mp 178 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
4.1.14. Methyl 2,6-bis(3-chlorophenyl)-1-phenyl-4-(phenyla-
mino)-1,2,5,6-tetrahydropyridine-3-carboxylate (13)
FTIR (KBr):
1371, 1216 cmÀ1
J = 14.9 Hz, 1H, H-5a), 2.83 (dd, J = 14.9 and 5.4 Hz, 1H, H-5b),
t
3781, 3374, 3019, 2361, 1652, 1594, 1511, 1465,
;
1H NMR (300 MHz, CDCl3 + CCl4): d 2.69 (d,
White solid, mp 220 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
t 3680, 3398, 3020, 2360, 1652, 1593, 1502, 1427,

M. Misra et al. / Bioorg. Med. Chem. 17 (2009) 625–633
631
1261, 1216 cmÀ1
;
1H NMR (300 MHz, CDCl3 + CCl4): d 2.82 (dd,
4.1.18. Ethyl 1,2,6-tris-(4-chlorophenyl)-4-(4-chlorophenyla-
J = 15.3 and 2.1 Hz, 1H, H-5a), 2.85 (dd, J =15.2 and 5.3 Hz, 1H, H-
5b), 3.97 (s, 3H, OMe), 5.13 (br s, 1H, H-6), 6.39–6.49 (m, 5H,
4ArH, and H-2), 6.65–6.69 (t, J = 7.2 Hz, 1H, ArH), 7.03–7.31 (m,
14H, ArH), 10.29 (br s, 1H, NH); 13C NMR (50 Hz, CDCl3 + CCl4): d
34.1 (CH2, C-5), 51.5 (OCH3), 55.3 (CH, C-2), 57.9 (CH, C-6), 97.6
(C, C-3), 113.3, 117.4, 125.0, 126.5, 126.6, 126.8, 127.1, 127.9,
129.4, 129.5, 129.8, 130.3 (ArCH), 134.8, 135.0, 137.9, 145.1,
146.5, 146.7, 156.3 (6ArC and C-4), 168.4 (CO); ESMS (m/z):
[M+H]+, 530. Elemental analysis for C33H26N2O2Cl2: Calcd C,
70.32; H, 4.95; N, 4.61. Found: C, 70.34; H, 4.93; N, 4.62.
mino)-1,2,5,6-tetrahydropyridine-3-carboxylate (17)
White solid, mp 190 °C, Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
3780, 3019, 2926, 2361, 1651 cmÀ1 1H NMR
(300 MHz, CDCl3 + CD3OD): 1.47–1.54 (t, J = 7.0 Hz, 3H,
t
;
d
COOCH2CH3), 2.76 (dd, J = 15.1 and 2.2 Hz, 1H, H-5a), 2.82 (dd,
J = 15.2 and 5.2 Hz, 1H, H-5b), 4.26–4.54 (m, 2H, OCH2), 5.06 (br
s, 1H, H-6), 6.25–6.42 (m, 5H, 4ArH, and H-2), 6.96–7.30 (m, 12H,
ArH), 10.25 (br s, 1H, NH); 13C NMR (50 MHz, CDCl3 + CD3OD): d
19.1 (CH3, COOCH2CH3), 37.6 (CH2, C-5), 59.4 (CH, C-2), 61.8 (CH,
C-6), 64.3 (OCH2), 102.3 (C, C-3), 118.3 (ArCH), 126.5 (ArC),
128.6, 128.8 (ArCH), 130.2 (C-4), 130.7, 131.0, 131.2, 131.3,
132.0, 132.9, 133.2, 133.4, 133.8, 134.3 (ArCH), 136.2, 138.9,
139.1, 140.3, 148.5, 149.0, 149.8 (ArC), 172.0 (CO); ESMS (m/z):
[M+H]+, 611. Elemental analysis for C32H26Cl4N2O2: C, 62.76; H,
4.16; N, 4.57. Found: C, 62.78; H, 4.14; N, 4.56.
4.1.15. Ethyl 2,6-bis(3-chlorophenyl)-1-(4-methoxyphenyl)-4-
(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (14)
Pale yellow solid, mp 167–170 °C, Rf = 0.5 (ethyl acetate/hex-
ane = 1/4); FTIR (KBr):
t ;
3447, 2987, 2836, 2362, 1646 cmÀ1 1H
NMR (300 MHz, CDCl3:CCl4): d 1.47 (t, J = 7.1 Hz, 3H, COOCH2CH3),
2.64 (dd, J = 15.1 and 2.7 Hz, 1H, H-5a), 2.77 (dd, J = 15.1 and
5.4 Hz, 1H, H-5b), 3.79 and 3.68 (two s, 6H, 2xOMe), 4.51–4.29
(dq, J = 7.1 HZ and 3.7HZ, 2H, OCH2), 5.01 (br s, 1H, H-6), 6.24–
6.41 (m, 5H, 4ArH, and H-2), 6.67–6.71 (m, 4H, ArH), 7.03–7.35
(m, 8H, ArH), 10.17 (br s, 1H, NH); 13C NMR (50 MHz, CDCl3
+ CCl4): d 15.2 (CH3, COOCH2CH3), 33.9 (CH2, C-5), 55.7, and 55.9
(OCH3), 56.1 (CH, C-2), 57.9 (CH, C-6), 60.0 (OCH2), 96.9 (C, C-3),
114.4, 114.8, 115.0 (ArCH), 125.1, 125.2, 127.0, 127.4, 127.7,
128.4, 129.7 (ArCH), 130.8, 134.7, 134.9, 141.2, 145.6, 147.0,
151.9, 156.8, 158.4 (8ArC and C-4), 168.2 (CO); ESMS (m/z):
[M+H]+, 602. Elemental analysis for C34H32Cl2N2O4: C, 67.66; H,
5.34; N, 4.64. Found: C, 67.64; H, 5.36; N, 4.63.
4.1.19. Ethyl-1-(4-methoxyphenyl)-4-(4-methoxyphenyl-
amino)-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate
(18)
White solid, mp 173 °C, Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
t
3751, 3447, 3230, 2991, 2362, 1646, 1600,
1511 cmÀ1
;
1H NMR (300 MHz, CDCl3 + CCl4): d 1.41–1.45 (t,
J = 7.0 Hz, 3H, COOCH2CH3), 2.62 (dd, J = 15.2 and 2.2 Hz, 1H, H-
5a), 2.76 (dd, J = 15.1 and 5.6 Hz, 1H, H-5b), 3.63 (s, 3H, ArOMe),
3.71 (s, 3H, ArOMe), 4.23–4.48 (m, 2H, OCH2), 5.02 (br s, 1H, H-
6), 6.18–6.21 (d, J = 8.64 Hz, 2H, ArH), 6.29 (s, 1H, H-2), 6.39–
6.42 (d, J = 9.0 Hz, 2H, ArH), 6.56–6.63 (m, 4H, ArH), 7.14–7.29
(m, 10H, ArH), 10.30 (br s, 1H, NH) ppm; 13C NMR (50 MHz, CDCl3
+ CCl4): d 15.2 (CH3, COOCH2CH3) , 34.0 (CH2, C-5), 55.6 (CH, C-2),
55.9 (ArOCH3), 56.2 (ArOCH3), 58.7 (CH, C-6), 59.8 (OCH2), 97.7 (C,
C-3), 114.3, 114.6, 114.9, 126.6, 127.0, 127.2, 127.4, 128.2, 128.5,
129.0 (ArCH), 131.2, 141.9, 143.7, 144.7, 151.5, 157.0, 158.2
(6ArC and C-4), 168.2 (CO); ESMS (m/z): [M+H]+, 611. Elemental
analysis for C34H34N2O4: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.36; H, 6.43; N, 5.22.
4.1.16. Ethyl-(4-chlorophenyl)-4-(4-chlorophenylamino)-2,6-di-
thiophen-2-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate (15)
White solid, mp 217 °C, Rf = 0.5 (ethyl acetate/hexane = 1/4);
FTIR (KBr):
t ;
3780, 3019, 2926, 2361, 1651 cmÀ1 1H NMR
(300 MHz, CDCl3): d 1.42–1.49 (t, J = 7.1 Hz, 3H, COOCH2CH3),
2.83 (dd, J = 15.2 and 2.5 Hz, 1H, H-5a), 3.1 (dd, J = 15.2 and
5.1 Hz, 1H, H-5b), 4.25–4.49 (m, 2H, OCH2), 5.3 (br s, 1H, H-6),
6.36 (s, 1H, H-2), 6.44 (d, J = 12.9 Hz, 2H, ArH), 6.63 (d,
J = 13.6 Hz, 2H, ArH), 6.81–7.02 (m, 4H, ArH), 7.0–7.26 (m, 6H,
ArH), 10.40 (br s, 1H, NH) ppm; 13C NMR (50 MHz, CDCl3): d 15.3
(CH3, COOCH3), 34.5 (CH2, C-5), 53.0 (CH, C-2), 54.2 (CH, C-6),
60.2 (OCH2), 98.4 (C, C-3), 109.9, 114.8 (ArCH), 122.6 (ArC),
124.1, 124.5, 124.8, 126.9, 127.2 (ArCH), 129.1, 129.6 (ArCH),
131.7, 136.9, 145.0, 147.1, 148.7, 155.7 (ArC and C-4), 168.0
(CO); ESMS (m/z): [M+H]+, 554. Elemental analysis for
C28H24Cl2N2O2S2: C, 60.54; H, 4.35; N, 5.04. Found: C, 60.56; H,
4.34; N, 5.03.
4.1.20. Ethyl 2,6-bis(phenyl)-1-phenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (19)
Pale yellow solid, mp 202 °C, Rf = 0.5 (ethyl acetate/hexane = 1/
4); FTIR (KBr):
t ;
3446, 3244, 2974, 2361, 1646 cmÀ1 1H NMR
(300 MHz, CDCl3 + CCl4): d 1.52 (t, J = 7.1 Hz, 3H, COOCH2CH3),
2.73 (dd, J = 15.0 and 2.0 Hz, 1H, H-5a), 2.89 (dd, J = 15.0 and
5.7 Hz, 1H, H-5b), 4.54–4.34 (dq, J = 7.1 and 3.7 Hz, 2H, OCH2),
5.13 (br s, 1H, H-6), 6.20–6.43 (m, 3H, ArH, and H-2), 7.00–7.09
(m, 4H, ArH), 7.17–7.35 (m, 10H, ArH), 10.29 (br s, 1H, NH); 13C
NMR (50 MHz, CDCl3): d 15.2 (CH3, COOCH3), 33.8 (CH2, C-5),
55.7 (CH, C-2), 58.7 (CH, C-6), 60.2 (OCH2), 99.2 (C, C-3), 114.4
(ArCH), 121.8 (ArC), 126.7, 126.9, 127.0, 127.3, 127.8, 128.7,
129.1, 129.2, 129.4 (ArCH), 131.8, 136.8, 142.7, 143.6, 145.8,
155.6 (5ArC and C-4), 168.3 (CO); ESMS (m/z): [M+H]+, 543. Ele-
mental analysis for C32H28Cl2N2O2: C, 70.72; H, 5.19; N, 5.15.
Found: C, 70.71; H, 5.17; N, 5.18.
4.1.17. Methyl 1-(4-methoxyphenyl)-4-(4-methoxyphenyl-
amino)-2,6-di-thiophen-2-yl)-1,2,5,6-tetrahydropyridine-3-
carboxylate (16)
White solid, mp 210 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
;
t 3694, 3020, 2361, 1655, 1596, 1497, 1437, 1216 cm
À1
1H NMR (300 MHz, CDCl3 + CCl4): 2.8–3.0 (m, 2H, H-5a, and
4.1.21. Ethyl-1-phenyl-4-(phenylamino)-2,6-di(pyridin-3-yl)-
1,2,5,6-tetrahydropyridine-3-carboxylate (20)
H-5b), 3.71 (s, 3H, ArOMe), 3.79 (s, 3H, ArOMe), 3.89 (s, 3H,
OMe), 5.27 (br s, 1H, H-6), 5.95 (s, 1H, H-2), 6.25–7.27 (m, 14 H,
ArH), 10.48 (br s, 1H, NH) ppm; 13C NMR (50 Hz, CDCl3 + CCl4): d
33.3 (CH2, C-5), 51.1 (OCH3), 54.2 (CH, C-2), 55.6 (ArOCH3), 55.7
(ArOCH3), 57.3 (CH, C-6), 97.4 (C, C-3), 114.5, 114.7, 114.9, 116.6,
119.6, 122.6, 123.8, 124.1, 124.5, 124.7 (ArCH), 125.3 (ArC),
126.4, 126.7, 126.8, 127.3, 128.0 (ArCH), 131.3, 140.9, 148.0,
149.9, 154.1, 156.9 (5ArC and C-4), 168.2 (CO), ESMS (m/z):
[M+H]+, 531.2. Elemental analysis for C29H28N2O4S2: C, 65.39; H,
5.30; N, 5.26. Found: C, 65.37; H, 5.32; N, 5.24.
White solid, mp 178 °C; Rf = 0.5 (methanol/chloroform = 1/2);
FTIR (KBr):
m ;
3368, 3244, 2972, 2362, 1720, 1654 cmÀ1 1H NMR
(300 MHz, CDCl3 + CCl4):
d
1.46–1.50 (t, J = 7.0 Hz, 3H,
COOCH2CH3), 2.83–2.84 (d, J = 3.8 Hz, 2H, H-5), 4.30–4.50 (m, 2H,
OCH2), 5.20 (br s, 1H, H-6), 6.42–6.48 (m, 5H, 4ArH, and H-2),
6.66 (t, J = 7.2 Hz, 1H, ArH), 7.06–7.28 (m, 7H, ArH), 7.43–7.45 (d,
J = 7.7 Hz, 1H, ArH), 7.58–7.61 (d, J = 7.8 Hz, 1H, ArH), 8.43–8.53
(m, 3H, ArH), 8.64 (s, 1H, ArH), 10.38 (br s, 1H, NH); 13C NMR
(50 MHz, CDCl3 + CCl4): d 15.1 (CH3, COOCH3), 34.1 (CH2, C-5),

632
M. Misra et al. / Bioorg. Med. Chem. 17 (2009) 625–633
53.9 (CH, C-2), 55.9 (C-6 and OCH3), 60.4 (OCH2), 97.6 (C, C-3),
113.5, 117.7, 123.4, 123.7, 126.0, 126.6, 129.0, 129.6, 134.5, 134.6
(ArCH), 137.8, 138.0, 139.6, 146.4 (5ArC and C-4), 148.2, 148.7,
148.9, 149.0 (ArCH), 155.7 (ArC), 168.0 (CO); ESMS (m/z): [M+H]+,
477. Elemental analysis for C30H28N4O2 C, 75.61; H, 5.92; N,
11.76. Found: C, 75.63; H, 5.91; N, 11.74.
test. Briefly drug dilutions (100
lL/well) were prepared in com-
plete RPMI 1640 and 10 L of parasite preparation was added
l
to each well. The final culture suspension had a hematocrit of
3–4% and a 1.0–2.0% infection of parasitized erythrocytes (>95%
rings) in culture medium containing 0.5% AlbuMax II and
15 lM hypoxanthine. Micro culture plates were incubated for
30–39 h at 37 °C in an Incubator supplied with 5% CO2 to allow
the development of malaria parasites. After incubation, culture
plates were taken out and maximum supernatant medium was
removed and thin blood smears of each well content were made
and stained with 5% Giemsa stain. These smears were checked
for the maturation of schizont relative to the controls. These
tests, measure the drug sensitivity of P. falciparum following
the WHO standard protocol with minor modifications for the
assessment of the inhibition of schizont maturation.
4.1.22. Methyl 2,6-bis(4-bromophenyl)-1-(4-methoxyphenyl)-
4-(4-methoxyphenylamino)-1,2,5,6-tetrahydropyridine-3-
carboxylate (21)
White solid, mp 179 °C; Rf = 0.5 (ethyl acetate/hexane = 1/5);
FTIR (KBr):
;
t 3797, 3421, 3018, 2358, 1650, 1508, 1371, 1216 cm
À1
1H NMR (300 MHz, CDCl3 + CCl4): 2.61 (dd, J = 15.0 and
2.4 Hz, 1H, H-5a), 2.72 (dd, J = 15.2 and 5.4 Hz, 1H, H-5b), 3.68 (s,
3H, ArOMe), 3.78 (s, 3H, ArOMe), 3.90 (s, 3H, OMe), 4.95 (br s,
1H, H-6), 6.18 (s, 1CH, H-2), 6.37 (d, J = 8.4 Hz, 2H, ArH), 6.64–
6.70 (m, 5H, ArH,), 7.00 (d, J = 8.1 Hz, 2H, ArH), 7.13 (d, J = 8.1 Hz,
2 H, ArH), 7.37–7.42 (m, 5H, ArH), 10.13 (s, 1H, NH) ppm; 13C
NMR (50Hz, CDCl3 + CCl4): d 34.0 (CH2, C-5), 51.4 (OCH3), 55.6 (Ar-
OCH3), 55.8 (ArOCH3), 56.0 (CH, C-2), 57.8 (CH, C-6), 96.8 (C, C-3),
114.5, 114.7, 115.0 (ArCH), 120.6, 121.3 (2ArC), 128.1, 128.7, 129.0
(ArCH), 130.8 (C-4), 131.6, 132.0 (ArCH), 141.2, 142.3, 143.4, 151.9,
156.9, 158.4, 168.5 (CO); ESMS (m/z): [M+H]+, 562. Elemental anal-
ysis for C33H30Br2N2O4: Calcd C, 58.42; H, 4.46; N, 4.13. Found: C,
58.44; H, 4.48; N, 4.11.
Acknowledgments
Authors thank ICMR and DBT New Delhi for financial assistance.
V.P. and J.P. thank CSIR New Delhi for JRF and SRF, respectively. It is
a CDRI Communication No. 7466.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2008.11.062.
4.1.23. Methyl 2,6-bis(3-nitrophenyl)-1-phenyl-4-(phenyla-
mino)-1,2,5,6-tetrahydropyridine-3-carboxylate (22)
Pale yellow solid, mp 180 °C, Rf = 0.4 (ethyl acetate/hexane = 1/
References and notes
4); FTIR (KBr):
t ;
3751, 3019, 2954, 2364, 1736, 1669 cmÀ1 1H
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4.01 (s, 3H, OCH3), 5.35 (br s, 1H, H-6), 6.41–6.50 (m, 5H, ArH,
and H-2), 6.70 (t, J = 7.26 Hz, 1H, ArH), 7.08–7.17 (m, 5H, ArH),
7.44–7.51 (m, 3H, ArH), 7.68 (d, J = 7.62 Hz, 1H, ArH), 7.96 (s, 1H,
ArH), 8.10 (m, 2H, ArH), 8.23 (s, 1H, ArH), 10.32 (br s, 1H, NH);
13C NMR (50 MHz, CDCl3): d 30.0 (CH3, COOCH3), 34.1 (CH2, C-5),
51.8 (CH, C-2), 55.6 (CH, C-6), 57.5 (C, C-3), 113.5, 118.3, 121.8,
121.9, 122.2, 122.8, 126.1, 127.0, 129.5, 129.6, 129.8, 129.9, 132.8
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t ;
3697, 3429, 3020, 2360, 1725, 1601 cmÀ1 1H NMR
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3xOCH3), 6.87–6.92 (m, 2 H, ArH), 7.35–7.41 (m, 2H, ArH), 7.51
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t ;
3605, 3020, 2360, 1597 cmÀ1 1H
NMR (300 MHz, CDCl3 + CCl4):
d
8.38 (s, 1H, CH), 7.87 (d,
J = 8.67 Hz, 2H, ArH); 7.41–7.36 (m, 2H, ArH), 7.24–7.18 (m,
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