Abstract
The goal of this research work was to prepare and evaluate the antitubercular (anti-TB) activity of ethionamide (ETH) and prothionamide (PTH) based coumarinyl-thiazole derivatives. ETH and PTH were reacted with coumarin intermediates (3a-3e) to provide the target compounds (4a-4e and 4f-4j, respectively). Spectral studies confirmed the assigned structures of 4a-4j. The Microplate Alamar Blue Assay was utilized to evaluate the anti-TB activity of compounds 4a-4j against Mycobacterium tuberculosis H37Rv strain in comparison to ETH, PTH, isoniazid (INH), and pyrazinamide (PYZ) as standard drugs. The cytotoxicity studies were carried out versus HepG2 and Vero cell lines. In addition. molecular docking studies of 4a-4j concerning the DprE1 enzyme and the in-silico evaluation of physicochemical and pharmacokinetic parameters were performed. Compounds 4a, 4b, 4f, and 4g displayed equal minimum inhibitory concentration (MIC) values in comparison to INH (3.125 mu g/ml) and PYZ (3.125 mu g/ml), whereas 4c-4e and 4h-4j displayed better MIC values (1.562 mu g/mL) than INH and PYZ. All compounds presented better anti-TB potential than ETH (6.25 mu g/mL) and PTH (6.25 mu g/mL). The studies of toxicity revealed that 4a-4j were safe up to 300 mu g/mL concentration versus Vero and HepG2 cell lines. The molecular docking studies suggested that 4a-4j could possess anti-TB activity through the inhibition of the DprE1 enzyme. The in silico studies showed that 4a-4j followed Lipinski's rule (drug-likeliness) and exhibited better gastrointestinal absorption than BTZ043 and macozinone. In conclusion, the ETH and PTH-based coumarinyl-thiazole template can help developing selective DprE1 enzyme inhibitors as potent anti-TB agents.