Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl) isoxazole-3-carboxamides: Hit-to-lead optimization and release of a novel antitubercular chemotype via scaffold derivatization

Tuberculosis is one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extensively drug-resistant strains is a reason for concern. We have previously reported a series of substituted 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides with growth inhibitory activity against Mycobac-terium tuberculosis strains and low propensity to be substrate of efflux pumps. Encouraged by these preliminary results, we have undertaken a medicinal chemistry campaign to determine the metabolic fate of these compounds and to delineate a reliable body of Structure-Activity Relationships. Keeping intact the (thiazol-4-yl)isoxazole-3-carboxamide core, as it is deemed to be the pharmacophore of the molecule, we have extensively explored the structural modifications able to confer good activity and avoid rapid clearance. Also, a small set of analogues based on isostere manipulation of the 2-aminothiazole were prepared and tested, with the aim to disclose novel antitubercular chemotypes. These studies, combined, were instrumental in designing improved compounds such as 42g and 42l, escaping metabolic degradation by human liver microsomes and, at the same time, maintaining good antitubercular activity against both drug-susceptible and drug-resistant strains.

Automated summary

Tuberculosis is a deadly infectious disease and the increase in drug-resistant strains is concerning. Previous studies have identified compounds with inhibitory activity against Mycobacterium tuberculosis strains. In this study, researchers aimed to determine the metabolic fate of these compounds and explore structural modifications to improve activity and avoid rapid clearance. Novel antitubercular chemotypes were also investigated. The findings led to the design of improved compounds with good activity against drug-susceptible and drug-resistant strains.