Synthesis and biological evaluation of some novel N-aryl-1,4- dihydropyridines as potential antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2011.07.068

1,4-Dihydropyridines are the emerging class of antitubercular agent. Recently, studies have revealed that 1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have demonstrated excellent antitubercular activity. We have synthesized new N

Full text of DOI:10.1016/j.bmcl.2011.07.068

Bioorganic & Medicinal Chemistry Letters 21 (2011) 5181–5183
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of some novel
N-aryl-1,4-dihydropyridines as potential antitubercular agents
⇑
Amit R. Trivedi , Dipti K. Dodiya, Bipin H. Dholariya, Vipul B. Kataria, Vimal R. Bhuva, Viresh H. Shah
Department of Chemistry, Saurashtra University, Kalawad Road, Rajkot 360005, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 26 July 2011
1,4-Dihydropyridines are the emerging class of antitubercular agent. Recently, studies have revealed that
1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have demonstrated excellent
antitubercular activity. We have synthesized new N-aryl-1,4-dihydropyridines bearing carbethoxy and
acetyl group at C-3 and C-5 of the DHP ring. In addition, 1H-pyrazole ring is substituted at C-4 position.
Keywords:
1,4-Dihydropyridines
Antitubercular activity
Antimycobacterial activity
Mycobacterium tuberculosis
The lowest minimum inhibitory concentration value, 0.02 lg/mL, was found for diethyl 1-(2-chloro-
phenyl)-1,4-dihydro-2,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine-3,5-dicarboxylate 4e mak-
ing it more potent than first line antitubercular drug isoniazid. In addition, this compound exhibited
relatively low cytotoxicity.
Ó 2011 Elsevier Ltd. All rights reserved.
Tuberculosis (TB) is a common and often deadly infectious dis-
ease caused by various strains of mycobacterium, usually Mycobac-
terium tuberculosis. Tuberculosis has been considered to be a
disease of poverty for many years with quite rare occurrence in
the developed countries. Unfortunately recently more people in
the developed world are contracting tuberculosis because their im-
mune systems are compromised by immunosuppressive drugs,
substance abuse or AIDS. Several decades ago effective anti-TB
drugs have been launched and one could hardly find a TB case to
be demonstrated at the medicinal universities. But TB stroke
back!1 The return of tuberculosis was declared by World Health
Organization (WHO) as a global emergency compared to a hypo-
thetic third world war with 9 million new TB cases and two million
deaths reported each year2,3; about one-third of the world’s popu-
lation is already infected with M. tuberculosis.4 Furthermore, in re-
cent times the occurrence of multidrug-resistant TB (MDR-TB), a
form of TB that does not respond to the standard treatments, is
more common. It is a shocking revelation that MDR-TB is present
in almost all countries as per the recent survey, made by the World
Health Organization (WHO) and its partners.
for development of new drugs with unique and divergent structure
and with a novel mechanism of action.
Recently, studies showed that 3,5-dicarbamoyl derivatives of
1,4-dihydropyridine (DHP) with lipophilic groups have consider-
able antitubercular activity against M. tuberculosis H37Rv.14–18 It
was also observed that esters or substituted isosters of pyridine
and pyrazine carboxylic acids (such as tetrazoles) have been more
active than the parent acids especially against resistant strains.
These esters are presumably activated by an esterase to parent
acid.19–22 Indeed, esters of pyrazinoic acids have been shown to
possess activity against pyrazinamide-resistant isolates which
has been attributed to a deficiency of nicotinamidase.19–22 In
addition, pyrazoles exhibited significant antitubercular activity.23
However, to the best of our knowledge, antitubercular activity of
1,4-dihydropyridines bearing N-aryl-substitution or C-3 and C-5
acetyl group is not much explored. Recognizing these facts and in
continuation of our work on antitubercular agents,24–28 it appeared
of interest to design and synthesize new derivatives of N-substi-
tuted 1,4-dihydropyridines bearing carbethoxy and acetyl group
at C-3 and C-5 of the DHP ring, respectively. It seems that such
replacements could effectively overcome the resistant isolates
which have been attributed to a deficiency of amidase or esterase.
In addition, pyrazole moiety is substituted at C-4 position of dihy-
dropyridine ring. The antimycobacterial activity of synthesized
compounds was evaluated against M. tuberculosis H37Rv (MTB).
The quest for the synthesis of N-aryl-1,4-dihydropyridines 4a–j
and 5a–j was carried out by heating the 1,3-diphenyl-1H-pyrazole-
4-carbaldehyde 1 (1 equiv), ethyl acetoacetate/acetyl acetone 2
(2 equiv) and substituted anilines 3 (1 equiv), on a steam bath for
2–3 h. Then after, methanol (25 mL) was added to the reaction mix-
ture; refluxing for an appropriate time culminated in the synthesis
Despite the efforts of academic institutions and the pharmaceu-
tical companies engaged in the design, synthesis, and development
of new antitubercular regimens, the current TB therapeutic arsenal
is poor. Only a few derivatives were found endowed with some
antimycobacterial activity, including fluoroquinolones (gatifloxacin
and moxifloxacin),5–8 diarylquinoline (TMC207),9 nitroimidazoles
(OPC67683 and PA824),10,11 pyrrole (LL3858)12 and 1,2-diamine
(SQ109).13 All the above facts reveal that there is an urgent need
⇑
Corresponding author.
E-mail address: drartrivedi@gmail.com (A.R. Trivedi).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.07.068

5182
A. R. Trivedi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5181–5183
N
N
NH2
O
O
H
O
O
N
N
a
R1
H3C
R1
+
CH3
R2
+
R1
N
CH3
R2
CHO
1
2
3
4a-j and 5a-j
4a-j R1 = OC2H5; R2 = H, 2-CH3, 3-CH3, 4-CH3, 2-Cl, 3-Cl, 4-Cl, 2-OCH3, 3-OCH3, 4-OCH3
5a-j R1 = CH3; R2 = H, 2-CH3, 3-CH3, 4-CH3, 2-Cl, 3-Cl, 4-Cl, 2-OCH3, 3-OCH3, 4-OCH3
Scheme 1. Synthesis of N-aryl-1,4-dihydropyridines 4a–j and 5a–j. Reagents and conditions: (a) MeOH, reflux.
Table 1
Physical constants and In vitro antitubercular screening data of dihydropyridines 4a–j and 5a–j
MICa
(
lg/mL)
IC50 VERO cells (
lg/mL)
SIc (SI = IC50/MIC)
mi Log Pd
b
Sr. No.
R1
R2
Yield (%)
M.P. (°C)
% Inhibition
4a
4b
4c
4d
4e
4f
4g
4h
4i
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
67
71
62
70
69
75
64
66
68
74
72
69
73
70
71
67
71
74
75
68
—
68
96
95
98
48
100
97
74
39
55
33
48
97
98
34
59
76
29
25
77
69
—
1.56
3.13
1.56
48
0.02
1.56
n.d
n.d
n.d
n.d
n.d
3.13
6.25
n.d
n.d
n.d
n.d
n.d
n.d
n.d
>10
>10
>10
n.d.
>10
7.08
n.d
n.d
n.d
n.d
n.d
>10
>10
n.d
n.d
n.d
n.d
n.d
n.d
n.d
—
>6.4
>3.2
>6.4
n.d.
>500
4.5
n.d
n.d
n.d
n.d
7.179
7.580
7.604
7.628
7.809
7.833
7.857
7.188
7.212
7.236
5.794
6.194
6.218
6.242
6.424
6.448
6.472
5.803
5.827
5.851
—
2-CH3
3-CH3
4-CH3
2-Cl
3-Cl
4-Cl
2-OCH3
3-OCH3
4-OCH3
H
2-CH3
3-CH3
4-CH3
2-Cl
3-Cl
4-Cl
2-OCH3
3-OCH3
4-OCH3
—
118
157
90
146
80
133
95
99
112
168
172
188
224
198
248
254
178
186
194
—
4j
5a
5b
5c
5d
5e
5f
5g
5h
5i
n.d
>3.2
>1.6
n.d
n.d
n.d
n.d
n.d
n.d
n.d
5j
INH
CH3
—
0.03
—
a
b
c
Minimum inhibitory concentration against H37Rv strain of M. tuberculosis (
Measurement of cytotoxicity in VERO cells: 50% inhibitory concentrations (
Selectivity index (in vitro): IC50 in VERO cells/MIC against M. tuberculosis.
mi Log P: Molinspiration Cheminformatics (www.molinspiration.com) calculated log P using online Molinspiration Property Engine v2009.01.
l
g/mL).
lg/mL).
d
of the molecules in good yields (62–75%, Scheme 1). Preparation of
1,3-diphenyl-1H-pyrazole-4-carbaldehyde 1 is described.29 De-
signed series of molecules 4a–j and 5a–j (Table 1) were character-
ized by 1H NMR, 13C NMR, and Mass spectrometry techniques, and
their purity by elemental analysis. The 1H NMR spectra of DHPs 4a–
j and 5a–j have the typical singlet of methine group lying in the re-
gion 5.42–5.47 ppm and multiplet of aromatic part of molecules
occurring in region between 6.21 and 7.93 ppm. The 13C NMR signal
of methine group can be observed at 32.0–36.2 ppm. IR spectra of
DHP derivatives were also in agreement with the structures.
All compounds were initially screened for their in vitro antimy-
pounds 4a, 4c, and 4f with MIC of <2
lg/mL. When compared to iso-
niazid (MIC: 0.03 g/mL), diethyl 1-(2-chlorophenyl)-1,4-dihydro-
l
2,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine-3,5-dicar-
boxylate 4e was found to be the most active compound in vitro with
MIC of 0.02 lg/mL against MTB and was more potent than isonia-
zid. Studies showed that pharmacokinetic properties and cellular
permeability of a drug can be modulated by its derivatization to
more lipophilic forms and lipophilicity can be considered an impor-
tant factor for antimycobacterial activity in penetrating the lipid-
rich mycobacterial cell-walls.31 The preliminary antimycobacterial
evaluation results showed that compounds with carbethoxy
substituents at C-3 and C-5 position of DHP ring exhibited higher
antimycobacterial activity than the compounds with acetyl substit-
uents at C-3 and C-5 position, probably due to their comparatively
higher lipophilicity (log P values) which can assist in penetrating li-
pid-rich mycobacterial cell-wall. However, lipophilicity cannot be
considered as a sole parameter contributing in the higher activity
for elaborating the structure–activity relationship. The extensive
structure–activity relation could be derived in future with various
possible modifications at the present active 1,4-dihydropyridine
cobacterial activity at 6.25 lg/mL against MTB H37Rv strain by the
Tuberculosis Antimicrobial Acquisition and Coordinating Facility
(TAACF) in BACTEC 12B medium using the Microplate Alamar Blue
Assay.30 Compounds exhibiting P90% inhibition in the initial
screen were retested at and below 6.25
to determine the actual MIC.
lg/mL using 2-fold dilution
In the preliminary screening, seven compounds 4a–c, 4e, 4f, 5b,
and 5c inhibited MTB with 90–100%. In the secondary level, one
compound 4e inhibited MTB with MIC of <1 lg/mL and three com-

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This work was funded by CSIR through grant no. 01(02348)/09/
EMR-II. The authors wish to thank CSIR for its financial support. We
are indebted to Tuberculosis Antimicrobial Acquisition and Coordi-
nating Facility (TAACF/ USA) for biological tests. A.T. is thankful to
CSIR, New Delhi for research fellowship.
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Supplementary data
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Supplementary data associated with this article can be found, in
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