title: 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.affiliation: Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Machang 97, Tongzhou District, Beijing 101149, China. luyu4876@hotmail.com
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.forename: Meiqin
authors.initials: M
authors.lastname: Zheng
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
authors.forename: Weijie
authors.initials: W
authors.lastname: Zhao
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhu
authors.forename: Haixia
authors.initials: H
authors.lastname: Jin
authors.forename: Dali
authors.initials: D
authors.lastname: Yin
authors.forename: Haihong
authors.initials: H
authors.lastname: Huang
authors.forename: Anna M
authors.initials: AM
authors.lastname: Upton
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002522:Chlorocebus aethiops; D002991:Clofazimine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity; D014376:Tuberculosis / Q000188:drug therapy*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D002991:Clofazimine