Synthesis, in vitro antitubercular activity and 3D-QSAR study of 1,4-dihydropyridines

• Published in: Molecular diversity 2010-05, Vol.14 (2), p.285-305
• Main Authors: Manvar, Atul T, Pissurlenkar, Raghuvir R. S, Virsodia, Vijay R, Upadhyay, Kuldip D, Manvar, Dinesh R, Mishra, Arun K, Acharya, Hrishikesh D, Parecha, Alpesh R, Dholakia, Chintan D, Shah, Anamik K, Coutinho, Evans C
• Format: Article
• Language: English
• Subjects: 1,4-DHPs; 3D-QSAR; Antitubercular activity; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; CoMFA; Computer Simulation; CoMSIA; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Full-Length Paper; Life Sciences; Models, Molecular; Mycobacterium tuberculosis - drug effects; Organic Chemistry; Pharmacy; Polymer Sciences; Quantitative Structure-Activity Relationship
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-009-9162-8

In continuation of our research program on new antitubercular agents, this article is a report of the synthesis of 97 various symmetrical, unsymmetrical, and N-substituted 1,4-dihydropyridines. The synthesized molecules were tested for their activity against M. tuberculosis H ₃₇Rv strain with rifampin as the standard drug. The percentage inhibition was found in the range 3-93%. In an effort to understand the relationship between structure and activity, 3D-QSAR studies were also carried out on a subset that is representative of the molecules synthesized. For the generation of the QSAR models, a training set of 35 diverse molecules representing the synthesized molecules was utilized. The molecules were aligned using the atom-fit technique. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r ²) of 0.98 and 0.95 with cross-validated r ²(q ²) of 0.56 and 0.62, respectively. The 3D-QSAR models were externally validated against a test set of 19 molecules (aligned previously with the training set) for which the predictive [graphic removed] is recorded as 0.74 and 0.69 for the CoMFA and CoMSIA models, respectively. The models were checked for chance correlation through y-scrambling. The QSAR models revealed the importance of the conformational flexibility of the substituents in antitubercular activity.