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 IC50 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.
Zhang DongFeng; Lu Yu; Liu, Kai; Liu BinNa; Wang JingBin; Zhang Gang; Zhang Hao; Liu Yang; Wang Bin; Zheng MeiQin; Fu Lei; Hou YanYan; Gong NingBo; Lv Yang; Li Chun; Cooper, C. B.; Upton, A.M.; Yin DaLi; Ma ZhenKun; Huan HaiHong. Identification of Less Lipophilic Riminophenazine Derivatives for the Treatment of Drug-Resistant Tuberculosis. Journal of Medicinal Chemistry (2012): Published online first [DOI: 10.1021/jm300828h]