Exploring rhodanine linked enamine-carbohydrazide derivatives as mycobacterial carbonic anhydrase inhibitors: Design, synthesis, biological evaluation, and molecular docking studies.

With the rise of multidrug-resistant tuberculosis, the imperative for an alternative and superior treatment regimen, incorporating novel mechanisms of action, has become crucial. In pursuit of this goal, we have developed and synthesized a new series of rhodanine-linked enamine-carbohydrazide derivatives, exploring their potential as inhibitors of mycobacterial carbonic anhydrase. The findings reveal their efficacy, displaying notable selectivity toward the mycobacterial carbonic anhydrase 2 (mtCA 2) enzyme. While exhibiting moderate activity against human carbonic anhydrase isoforms, this series demonstrates promising selectivity, positioning these compounds as potential antitubercular agents. Compound 6d was the best one from the series with a Ki value of 9.5 µM toward mtCA 2. Most of the compounds displayed moderate to good inhibition against the Mtb H37Rv strain; compound 11k showed a minimum inhibitory concentration of 1 µg/mL. Molecular docking studies revealed that compounds 6d and 11k show metal coordination with the zinc ion, like classical CA inhibitors.

Synthesis and structure-activity relationship of new chalcone linked 5-phenyl-3-isoxazolecarboxylic acid methyl esters potentially active against drug resistant Mycobacterium tuberculosis.

In search of novel therapeutic agents active against emerging drug-resistant Mycobacterium tuberculosis and to counter the long treatment protocol of existing drugs, herein we present synthesis and biological evaluation of a new series of 5-phenyl-3-isoxazolecarboxylic acid methyl ester-chalcone hybrids. Among 35 synthesized compounds, 32 analogues displayed potent in-vitro activity against Mycobacterium tuberculosis H37Rv with MIC 0.12-16 µg/mL. Cell viability test against Vero cells indicated 29 compounds to be non-cytotoxic (CC50 > 20 µg/mL & SI > 10). Most potent compounds with MIC 0.12 µg/mL (7 b, 7j, 7 ab) exhibited selectivity index (SI) in excess of 320. Further studies on activity against drug-resistant Mycobacterium tuberculosis revealed 7j as the most potent compound with MIC 0.03-0.5 µg/mL. Time-kill kinetic study suggested compound 7j displaying concentration-dependent bactericidal killing activity with relatively comparable potency to that of current first-line anti-TB drugs. Taken together, 7j presents a novel hit with potential to be translated into a potent antimycobacterial.