The global tuberculosis crisis urgently demands new, efficacious, orally available drugs with the potential to shorten the long complex treatments of drug sensitive and drug resistant disease. Clofazimine, a riminophenazine used for many years to treat leprosy, demonstrates efficacy in animal models of tuberculosis via a novel mode of action. However, clofazimine’s physicochemical and pharmacokinetic properties contribute to side effects that limit its use; in particular, an extremely long half-life and propensity for tissue accumulation together with clofazimine’s dye properties lead to unwelcome skin discoloration. We recently conducted a systematic structure-activity study of over five hundred riminophenazine analogs for anti-M. tuberculosis activity. Here, we describe the characteristics of twelve prioritized compounds in more detail. The new riminophenazine analogs have enhanced in vitro activity compared to clofazimine against replicating M. tuberculosis H37Rv as well as panels of drug sensitive and drug resistant clinical isolates. The new compounds demonstrate at least equivalent activity compared to clofazimine against intracellular M. tuberculosis and in addition, most are active against non-replicating M. tuberculosis. Eleven of these more water-soluble riminophenazine analogs possess shorter half-lives than clofazimine when dosed orally to mice, suggesting they may accumulate less. Most importantly, the nine compounds progressed to efficacy testing demonstrate inhibition of bacterial growth in the lungs that is superior to the activity of an equivalent dose of clofazimine when administered orally for 20 days in a murine model of acute tuberculosis. The efficacy of these compounds coupled with their decreased potential for accumulation and therefore perhaps also tissue discoloration, warrants their further study.
Antimicrobial Agents and Chemotherapy, published online ahead of print on 15 August 2011. [doi:10.1128/AAC.00699-11]