Harsukh Gevariya, B. Desai, V. Vora
2001
Citations
1
Influential Citations
18
Citations
Quality indicators
Journal
Heterocyclic Communications
Abstract
2,6-Dimethyl-3-acetyl-5-carbmethoxy-4-(3'nitrophenyl)-1,4-dihydropyridine 1 was condensed with aromatic and heterocyclic aldehydes to form chalcone analogs 2a-h and then cyclised to substituted pyrazolines leading to novel 1,4-dihydropyridine 3a-h. 4a-h and 5a-h which are directly attached to heterocyclic moiety and devoid of the ester function at C3 (of DHP). All compounds were screened for their antitubercular activity against Mycobacterium tuberculosis (H37Rv). INTRODUCTION The dihydropyridines are the well-known drug moiety for the treatment of antihypertensive and cardiovascular disorders'. However, it is also associated with antiallergic, antiinflammatory, treatment of circulating diseases, calcium channel antagonism etc. About 50 different dihydropyridines are launched as new drugs in last 20 years. The 3-nitrophenyl substitution at C4 of DHP provides excellent stability and pharmacodynamic properties leading to many drugs like Nicardipine, Pranidine, Nimodipine, Tiamdipine' and Manidipine". These drugs mainly exhibits calcium channel antagonist activity. The DHPs are still the subject of intensive study, due to recent developments with respect to mdr reversal in tumor cells which has given a new dimension of application of dihydropyridines'"'. Our aim was to prepare some interesting new unsymmetrical dihydropyridine derivatives from 2,6dimethyl-3-acetyl-5-carbmethoxy-4-(3'-nitrophenyl)-1,4-dihydropyridine 1. Due to active group at 3" position of DHP ring, the aldehydes were condensed with acetyl group in presence of base catalyst in ethanol to form chalcone analogs 2a-h. They were refluxed with hydrazine or Phenylhydrazine with acetic acid to afford substituted pyrazolines 3a-h. 4a-h. 5a-h linked directly with dihydropyridine nucleus. Elemental and spectral analysis supported the constitution of the product. The products were screened for their antitubercular activity. The compounds were tested against M. Tuberculosis H37Rv. The standard drug used was Rifampicin. Primary screening was conducted at 12.5 μg/ml against Mycobacterium Tuberculosis (H37Rv) strain in BACTEC 12B medium using the BACTEC 460-radiometric system. RESULTS AND DISCUSSION It can be seen from Table-1 that substitution at 4-phenyl ring considerably affects the antitubercular activity and other analogs having 4-N, N-dimethylaminophenyl and 4-methoxyphenyl moieties showed 66% and 45% inhibition respectively. The percentage of inhibition indicated that chalcone 2e containing Vol. 7, No. 5, 2001 Synthesis of some new unsymmetrical 1,4-dihydropyridine derivatives as potent antitubercular agents 3-nitrophenyl substitution showed significant activity (85%). The other substitutions did not show good activity. The 1Η pyrazoline linked dihydropyridines were found to be almost inactive. The acetyl pyrazoline exhibited very good activity. The unsubstituted 4-phenyl ring of acetylpyrazoline 4f showed 87% inhibition. The 1'-phenyl derivatives also exhibited significant activity. So far as structure activity relationship is concerned, 3-nitrophenyl group is able to exhibit significant activity. EXPERIMENTAL The melting points were determined in open capillary tubes and were uncorrected. IR spectra were recorded in NICOLET-MEGNA-IR 550 SERIES II and Ή NMR recorded on Bruker AC-300 MHz FT NMR using TMS as an internal standard, chemical shift in δ ppm. The compound 2,6-Dimethyl-3-acetyl-5-carbmethoxy-4-(3'-nitrophenyl)-1,4-dihydropyridine 1 was prepared according to the method described in literature'". Preparation of 2,6-Dimethyl-5-carbmethoxy-4-(3'-nitrophenyl)-3-[3"-(4"'-methoxyphenyl)propane-1one]-1,4-dihydropyridine 2a, To a well-stirred solution of 2,6-dimethyl-3-acetyl-5-carbmethoxy-4-(3'-nitrophenyl)-1,4-dihydropyridine (3.3 g, 0.01 M) and p-anisaldehyde (1.36 g, 0.01 M) in absolute ethanol, 40% NaOH solution was added till pH reaches to 8.0. Then reaction mixture was stirred for 24 hrs at 25-30°C. The reaction mixture was poured into crushed ice containing little amount of HCl. 10% Sodium bicarbonate solution was added and sticky mass was left overnight for isolation. The product was filtered, dried and recrystallised from ethanol, m.p. 160°C; yield 60%, Calculated for C25H24N206, C, 66.96; H, 5.36; N. 6.25; Found C, 67.00; H, 5.30; N, 6.29 Ή NMR (300 MHz, CDCI3+DMSO-d6) δ; 3.80 (s, 3H, CH3); 6.10-6.40 (dd, 2H, COCH=CH); 2.35 (s, 6H, 2xCH3); 3.59 (s, 3H, OCH3); 5.23 (s, 1H, C4H). IR (KBr) cm": 1703 (C=0 ester); 1685 (C=0 chalcone); 1535, 1330 cm ' (C-NCy. Similarly other chalcones 2b-h were prepared. The physical and analytical data were recorded in Table-2 Preparation of 2,6-Dimethyl-4-(3'-nitrophenyl)-5-carbmethoxy-3-[3"-(4"'-methoxyphenyl)-2Hpyrazoline-5'-yl]-1,4-dihydropyridine 3a. A mixture of 2a (4.48g, 0.01 M) in ethanol, hydrazine hydrate (0.5g, 0.01 M) and piperidine (1ml) was refluxed for 8-10 hrs in absolute ethanol. The isolated product was filtered, dried and recrystallised from ethanol to give 3a, m.p. 144°C, yield 62%, Calculated for C25H26N405: C, 64.93; H, 5.62; N, 12.12; Found C, 64.85; H, 5.73; N, 12.01; Ή NMR (300 MHz CDCI3+DMSO-d6) δ : 2.36 (s, 6H, 2xCH3); 3.56 (s, 3H, OCH3); 3.64 (s, 3H, COOCH3); 5.10 (s, 1H, C4H); 2.7-2.8 (t, 1H, CH-CH2). IR (KBr) cm ' : 3135 (NH); 1530, 1324 (C-N02). Similarly other compounds 3b-h were prepared. The physical and analytical data were recorded in Table-2. Preparation of 2,6-Dimethyl-4-(3'nitrophenyl)-5-carbmethoxy-3-[3'-(4"-methoxyphenyl)-2'acetylpyrazoline-5'-yl]-1,4-dihydropyridine 4a, A mixture of 2a (4.48g, 0.01 M) in acetic acid (10ml) and hydrazine hydrate (0.5g, 0.01 M) was refluxed on constant temperature bath for 8hrs and kept overnight. The product was isolated, dried and recrystallised in