Letters in Drug Design & Discovery, 2008, 5, 7-14
7
CoMFA Study, Syntheses, Antitubercular and Anticancer Activity of Some Novel 1,4-Dihydropyridines B.R. Prashantha Kumar*,1, S. Yuvaraj1, Anil Srivastava2, Vanitha Chaturvedi2, Y.K. Manju2, B. Suresh1 and M.J. Nanjan1 1
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ootacamund-643001, India
2
Central Drug Research Institute, Lucknow, India Received September 12, 2007: Revised November 25, 2007: Accepted November 27, 2007
Abstract: 1,4-dihydropyridines are the emerging class of antitubercular agents. In this protocol we present, the syntheses, characterization details for the conformation of structures, antitubercular and anticancer activity results for some novel 1,4-dihydropyridines. The comparative molecular field analysis (CoMFA) model for 1,4-dihydropyridines was derived. The 3D QSAR model demonstrated good ability to predict activity of studied compounds (r2 = 0.97, q2 = 0.81). Based on the CoMFA steric and electrostatic contour maps, structure activity relationships were established for antitubercular activity.
Keywords: 1,4-Dihydropyridines, Antitubercular activity, CoMFA, 3D-QSAR, Anticancer activity. INTRODUCTION Among the small organic molecules, heterocyclic moiety holds a special place as historical pharmacophore, apart from synthetic interests [1, 2]. The 1,4-dihydropyridine moiety is a key feature of antihypertensive drugs [3, 4] like nitrodipine [5] and nifedipine [6], for blocking Ca2+ channels. Recently, compounds containing 1,4-dihydropyridine moiety, were also found to possess potential antitubercular [7, 8, 9] and anticancer activities [10]. The 1,4-dihydropyridines were first synthesized by the Hantzsch in the year 1886 by adopting multi component reaction mechanism [11, 12]. The classical Hantzsch synthesis involves reaction of one mole of an aldehyde, two moles of a -ketoester and one mole of aqueous ammonia. Though this method of synthesis was later modified by Bayer [13] followed by Knoevenagel [14], Hantzsch method of synthesis was, however, found to be the most suitable for the synthesis of 1,4-dihydropyridines.
or heteryl aldehyde, two equivalent of 2-chloro acetoacetanilide and excess of aqueous ammonia solution, refluxing in presence of methanol as solvent for 24 h as shown in the Scheme 2. The yields of 1,4-dihydropyridines were also found to be low ranging from 20-47 %. H 3C
O O
O
*Address correspondence to this author at the Faculty and Research associate, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ootacamund-643001. TN., Índia; Tel: +91-423-2443393 Ext: 223; Fax: +91-423-2442937; E-mail:
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Cl
a H N
H 3C O
O
Cl
1
Scheme 1. Synthesis of 2-chloro acetoacetanilide [a = Neat, reflux for 2 h]. R CHO
O
O N H
N H O
H 3C
Cl
The 2-chloro acetoacetanilide (1) was synthesized by refluxing equimilimolar amounts of 2-chloro aniline and ethyl acetoacetate according to the reported procedure as shown in the Scheme 1 [15]. The yield of 2-chloro acetoacetanilide, however, was found to be low of only 38% yield. The syntheses of 1,4-dihydropyridnes were carried out by multicomponent, cyclisation reaction involving, one equivalent of aryl
H 2N
+
In this present protocol we have made an attempt to synthesize, analyze, some novel substituted 1,4-dihydropyridines for their potential antitubercular and anticancer activities. The CoMFA study was performed to define 3D structural features required for 1,4-dihydropyridines to exhibit antitubercular activity. RESULTS AND DISCUSSION
CH3
NH3
CH3
O
Cl
a O
Cl
R
N H
O N H
N CH3 H 1,4-Dihydropyridines (2-11) H3C
Cl
Scheme 2. Synthesis of 1,4-dihydropyrdines by Hantzsch multicomponent method [a = Methanol, reflux 24 h]. © 2008 Bentham Science Publishers Ltd.
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Letters in Drug Design & Discovery, 2008, Vol. 5, No. 1
Table 1.
Kumar et al.
The Synthesised 1,4-Dihydropyridienes (Test Set, Excluding Compound 4 and 9) Along with Antitubercular and Anticancer Activities O
Cl
Compd.
R
O
N H H3C
N H N H
CH3
% Growth inhibition of EAC cells by test compounds at different concentrations ( g/ml)
R
2
3
F
Cl
4
5
Br
Cl
Antitubercular activity CTC50 ( g/ml) Obs. Activity
Pred. Activity
Res. Activity
45.0
-0.60
-0.02
-0.58
92.86
500
0.07
0.03
0.04
9
O
14.29
10.72
10.72
7.15
3.58
>500
-
-
-
14.29
10.72
7.15
7.15
3.58
>500
-0.60
-0.01
-0.59
100
100
100
100
82.15
