Synthesis and evaluation of rifabutin analogs against Mycobacteriumavium and H37Rv, MDR and NRP Mycobacterium tuberculosis

Clinical utility of rifabutin 1 (RBT), a potent antibiotic used in multidrug regimens for tuberculosis (TB) as well as for infections caused by Mycobacterium avium complex (MAC), has been hampered due to dose-limiting toxicity. RBT analogs 2–11 were synthesized and evaluated against M. avium 1581 and Mycobacterium tuberculosis susceptible and resistant strains in vitro. A selection of candidates were also assayed against non-replicating persistent (NRP) M. tuberculosis. Subsequent in vivo studies with the best preclinical candidate drugs 5 and 8, in a model of progressive pulmonary tuberculosis of Balb/C mice infected either with H37Rv drug–sensible strain or with multidrug resistant (MDR) clinical isolates, resistant to all primary antibiotics including rifampicin, were performed. The results disclosed here suggest that 5 and 8 have potential for clinical application.

Analogs 5 and 8 as drug candidates revealed lesser cytotoxicity, similar MICs, and higher CFU reduction in both susceptible (H37Rv) and MDR Mycobacterium tuberculosis clinical isolates than the lead compound rifabutin.Figure optionsDownload as PowerPoint slide