Guanilated Quinolones with Dual Antitubercular and Anti-Inflammatory Activities

Host-directed therapy (HDT) for tuberculosis (TB) generally involves the addition of adjuvant(s) to the standard TB regimen of at least four drugs with the hope of reducing treatment duration. Potential clinical challenges with the addition of adjuvant (s) to the TB regimen are increased pill load, which may lead to nonadherence, and consequently the precipitation of drug resistance; as well as the issue of drug-drug interactions. Molecules that can concurrently act as HDT and antitubercular agent thus have the potential to reduce TB treatment duration, and the pill burden, which may ultimately lead to a simplified TB regimen. To this end, we investigated novel guanilated quinolones as dual inhibitors of Janus Kinase 3 (host target) and Mycobacterium tuberculosis. Compound 13 was identified with potent Janus Kinase 3 inhibitory activity-exhibiting 98% enzyme inhibition at 1 µM, and antitubercular activity in the range of 0.2-6 µM in two different growth media.