Synthesis, computational and in vitro anti-tubercular activity studies of thiadiazole-linked pyridazinone derivatives

Mycobacterium tuberculosis (Mtb) is an infectious bacterium that causes pulmonary tuberculosis (TB). The emergence of drug-resistant Mtb strains necessitates the need for the identification of novel antitubercular agents. In this study, we have repurposed pyridazinone-1,3,4-thiadiazole hybrids for their in-vitro antitubercular activity against Mtb. We have designed and synthesised a series of pyridazinone-1,3,4-thiadiazole hybrids (7a-r). Among these, several compounds (especially 7a, 7c, 7d, 7e, 7n, 7p, 7q, and 7r) inhibited Mtb in vitro, while compound 7d showed moderate antimycobacterial activity (MIC 6.25 mM). Further MIC determination against Mycobacterium bovis BCG wild-type and mutant strains revealed that compound 7d does not inhibit known Mtb targets such as InhA, KatG, HadC or MmpL3. The current results do not conclusively identify the molecular target or mechanism of action of compound 7d and the present results do not provide sufficient evidence to differentiate among the proposed targets of compound 7d. In silico studies showed that these compounds complied with Lipinski's rule, promoting favourable drug-like characteristics. These findings suggest that the pyridazinone-1,3,4-thiadiazole hybrid scaffolds can be optimised further to develop novel antitubercular agents.