Design, synthesis, and structure-activity correlations of novel dibenzo[b,d furan, dibenzo[b,d]thiophene, and N-methylcarbazole clubbed 1,2,3-triazoles as potent inhibitors of mycobacterium tuberculosis
Patpi S.R.,Indian Institute of Chemical Technology |
Pulipati L.,Indian Institute of Chemical Technology |
Yogeeswari P.,Birla Institute of Technology and Science |
Sriram D.,Birla Institute of Technology and Science |
And 6 more authors.
Journal of Medicinal Chemistry | Year: 2012
A molecular hybridization approach is an emerging structural modification tool to design new molecules with improved pharmacophoric properties. In this study, 1,2,3-triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural product-based tricyclic (carbazole, dibenzo[b,d]furan, and dibenzo[b,d]thiophene) antimycobacterial agents were integrated in one molecular platform to prepare various novel clubbed 1,2,3-triazole hybrids using click chemistry. Structure-activity correlations and in vitro activity against M. tuberculosis strain H37Rv of new analogues revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-methyl-9H-carbazole series. Two of the most potent M. tuberculosis inhibitors 13h and 13q with MIC = 0.78 μg/mL (∼1.9 μM) displayed a low cytotoxicity and high selectivity index (50-255) against four different human cancer cell lines. These results together provided the potential importance of molecular hybridization and the development of triazole clubbed dibenzo[b,d]thiophene-based lead candidates to treat mycobacterial infections. © 2012 American Chemical Society.