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ABSTRACT
| Title |
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Pharmacophore modeling and 3D-QSAR studies on substituted benzothiazole / benzimidazole analogues as DHFR inhibitors with antimycobacterial activity |
| Authors |
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R. Priyadarsini, Dr. C.B. Tharani, Sathya Suganya, S.Kavitha |
| Keywords |
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Pharmacophore, 3D-QSAR-MFA, DHFR , Benzothiazole/Benzimidazole derivatives, Antitubercular agents |
| Issue Date |
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August 2012 |
| Abstract |
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The resurgence of tuberculosis and the emergence of multidrug-resistant strains of Mycobacteria drugs has propelled the development of new structural classes of antitubercular agents. The present study was undertaken to investigate the opportunities which the enzyme dihydrofolate reductase, a promising drug target for treatment of Mycobacterial infections offers for the development of new TB drugs. Pharmacophore models were established by using the HipHop and HypoGen algorithms implemented in the Catalyst software package. The best quantitative pharmacophore model, consisted of two hydrogen bond acceptor, a hydrophobic aliphatic, and a ring aromatic feature which has the highest correlation coefficient (0.93), as well as enrichment factor of 1.75 and Goodness of hit score of 0.73. Based on the pharmacophore model some leads were optimized and some of its derivatives were synthesized and analysed by following QSAR studies. About 25 compounds of substituted benzothiazole/ benzimidazole derivatives were synthesized as potent DHFR inhibitors and screened for antimycobacterial activity. To further explore the structure-activity relationships of all newly synthesized compounds, 3D-QSAR analyses were developed. MFA studies were performed with the QSAR module of Cerius2 using genetic partial least squares (G/PLS) algorithm. The predictive ability of the developed model was assessed using a training set of 25 and a test set of 5 compounds (r2pred = 0.924).The analyzed MFA model demonstrated a good fit, having r2 value of 0.868 and cross validated coefficient r2cv value of 0.771 . |
| Page(s) |
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441-450 |
| ISSN |
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0975-9492 |
| Source |
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Vol. 3, No.8 |
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