Exploration of Isoxazole-Carboxylic Acid Methyl Ester Based 2-Substituted Quinoline Derivatives as Promising Antitubercular Agents

In pursuit of potent anti-TB agents active against drug resistant tuberculosis (DR-TB), herein we report synthesis and bio-evaluation of a new series of isoxazole-carboxylic acid methyl ester based 2-substituted quinoline derivatives. Preliminary evaluation indicated selectivity towards Mtb H37Rv, with no inhibition of non-tubercular mycobacterial (NTM) & bacterial pathogen panel. Out of 36 synthesized compounds, majority exhibited substantial inhibition of Mtb H37Rv (MIC 0.5-8 μg/mL). Cell viability test against Vero cells revealed no significant cytotoxicity. Further, screening against drug resistant strains (DR-Mtb) found hit compound displaying promising potency (MIC 1-4 μg/mL). Structure optimization of the hit led to the identification of lead compound demonstrating potent inhibition of both drug-susceptible Mtb (MIC 0.12 μg/mL) and drug-resistant Mtb (MIC 0.25-0.5 μg/mL) along with a high selectivity index (SI) >80. Taken together, with appreciable selectivity and potent activity, these chemotypes show prospect to be turned into a potential anti-TB candidate.