title: Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis.
abstract: Clofazimine (CFZ), a member of the riminophenazine class, has been studied in clinical trials for the treatment of multidrug-resistant tuberculosis (MDR-TB). CFZ has several side effects which can be attributed to its extremely high lipophilicity. A series of novel riminophenazine analogues bearing a C-2 pyridyl substituent was designed and synthesized with the goal of maintaining potent activity against Mycobacterium tuberculosis (M. tuberculosis) while improving upon its safety profile by lowering the lipophilicity. All compounds were evaluated for their in vitro activity and cytotoxicity. The results demonstrated that many new compounds had potent activity against M. tuberculosis with MICs of less than 0.03 μg/mL and low cytotoxicity with IC(50) values greater than 64 μg/mL. Some compounds were tested for in vivo efficacy against MDR-TB in an experimental mouse infection model. Two compounds demonstrated equivalent or better efficacy than CFZ in this model with significantly reduced skin discoloration potential.
authors.affiliation: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.forename: Binna
authors.initials: B
authors.lastname: Liu
authors.forename: Jingbin
authors.initials: J
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Meiqin
authors.initials: M
authors.lastname: Zheng
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Hou
authors.forename: Ningbo
authors.initials: N
authors.lastname: Gong
authors.forename: Yang
authors.initials: Y
authors.lastname: Lv
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Cooper
authors.forename: Anna M
authors.initials: AM
authors.lastname: Upton
authors.forename: Dali
authors.initials: D
authors.lastname: Yin
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
authors.forename: Haihong
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002991:Clofazimine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D024901:Drug Resistance, Multiple, Bacterial; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D002991:Clofazimine