Introduction: Tuberculosis is one of the leading causes of death worldwide. Due to the increasing resistance of Mycobacterium tuberculosis to the existing anti-TB drugs and TB-HIV synergism there is an urgent need to develop new anti-TB drugs with novel mechanism of action. Methods: An “all-water” one-pot strategy has been developed for the synthesis of the ethyl benzo[d]imidazole-2-carboxylates as the key starting materials, through water-assisted tandem N-arylation-reduction-cyclocondensation (with ethyl glyoxalate). All the synthesized benzo[d]imidazole-2-carboxamides have been tested for in vitro anti-TB activity against M. tuberculosis H37Rv (ATCC27294 strain) and cytotoxicity evaluation against RAW 264.7 cell lines followed by assay against isoniazid resistant Mycobacterium tuberculosis. Results: Twenty seven designed compounds have been synthesized via NH4Cl-catalyzed amidation of the key intermediates ethyl benzo[d]imidazole-2-carboxylates. Compound 8e exhibited best anti-TB activity with the MIC of 0.78 µg/mL and therapeutic index &gt; 60 and 8a, 8f, 8k and 8o with MIC of 1.56 µg/mL have been found to be the next most active compounds. The active compounds with MIC 6.25 µg/mL were found to be non cytotoxic (&lt; 50% inhibition) against RAW 264.7 cell lines. The compound 8e was found with MIC of 3.125 µg/mL against isoniazid resistant Mycobacterium tuberculosis using MABA assay. Nineteen compounds (with Mtb MIC of ≤ 25 µg/mL) were also subjected to test their potential as broad spectrum antibacterial agents against other gram positive bacteria B. subtilis 168 and BsFtsZ inhibition that revealed 8o as the most potent compound with 91 ± 5% of inhibition and perturbed secondary structure highlighting its potential as new anti-TB agents. The selected anti-TB active compounds were also subjected to inhibitory studies against other Gram positive bacteria as well as the bacterial FtsZ and 8h, 8i, 8o, and 10h inhibited the growth of B. subtilis 168 cells &gt;70% and 8o strongly increased the length of bacterial cells. The colony formation was reduced by 62 ± 5 and 88 ± 7% in the presence of 3 and 5 µM of 8o respectively whereas no colony was found in the presence of 6 µM concentration of 8o. The binding of 8o to BsFtsZ perturbed the secondary structures of the protein confirmed through far-UV circular dichroism spectroscopy. Conclusions: These results can be considered as an important start point for the discovery of anti-TB chemotypes against tuberculosis.

Benzo[d]imidazole-2-carboxamides as new anti-TB agents: Design, synthesis, biological evaluation, and target identification

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ACS Fall 2022

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