Design, Synthesis, and
Structure–Activity Correlations
of Novel Dibenzo[<i>b</i>,<i>d</i>]furan, Dibenzo[<i>b</i>,<i>d</i>]thiophene, and <i>N</i>-Methylcarbazole
Clubbed 1,2,3-Triazoles as Potent Inhibitors of <i>Mycobacterium
tuberculosis</i>
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Abstract
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 <i>Mycobacterium tuberculosis</i> inhibitors and synthetic and natural product-based tricyclic (carbazole,
dibenzo[<i>b</i>,<i>d</i>]furan, and dibenzo[<i>b</i>,<i>d</i>]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 <i>M. tuberculosis</i> strain H37Rv of new analogues revealed the order: dibenzo[<i>b</i>,<i>d</i>]thiophene > dibenzo[<i>b</i>,<i>d</i>]furan > 9-methyl-9<i>H</i>-carbazole
series. Two of the most potent <i>M. tuberculosis</i> inhibitors <b>13h</b> and <b>13q</b> 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[<i>b</i>,<i>d</i>]thiophene-based lead candidates to treat mycobacterial
infections