Clofazimine analogs with efficacy against experimental tuberculosis and reduced potential for accumulation.

Abstract

The global tuberculosis crisis urgently demands new, efficacious, orally available drugs with the potential to shorten and simplify the long and complex treatments for 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 leads to unwelcome skin discoloration. We recently conducted a systematic structure-activity study of more than 500 riminophenazine analogs for anti-Mycobacterium tuberculosis activity. We describe here the characteristics of 12 prioritized compounds in more detail. The new riminophenazine analogs demonstrated 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 of them were active against nonreplicating M. tuberculosis. Eleven of these more water-soluble riminophenazine analogs possess shorter half-lives than clofazimine when dosed orally to mice, suggesting that they may accumulate less. Most importantly, the nine compounds that progressed to efficacy testing demonstrated 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, along with their decreased potential for accumulation and therefore perhaps also for tissue discoloration, warrants further study.

• Authors: Yu Lu, Meiqin Zheng, Bin Wang, Lei Fu, Weijie Zhao, Peng Li, Jian Xu, Hui Zhu, Haixia Jin, Dali Yin, Haihong Huang, Anna M Upton, Zhenkun Ma
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 55 Issue 11 Pg. 5185-93 (Nov 2011) ISSN: 1098-6596 [Electronic] United States
• PMID: 21844321 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Clofazimine

Topics

• Administration, Oral
• Animals
• Antitubercular Agents (pharmacokinetics, pharmacology, therapeutic use)
• Cell Line
• Chlorocebus aethiops
• Clofazimine (pharmacokinetics, pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects, pathogenicity)
• Tuberculosis (drug therapy)
• Vero Cells