Identification of Less Lipophilic Riminophenazine Derivatives for the Treatment of Drug-Resistant Tuberculosis

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• 作者：Dongfeng Zhang ; Yu Lu ; Kai Liu ; Binna Liu ; Jingbin Wang ; Gang Zhang ; Hao Zhang ; Yang Liu ; Bin Wang ; Meiqin Zheng ; Lei Fu ; Yanyan Hou ; Ningbo Gong ; Yang Lv ; Chun Li ; Christopher B. Cooper ; Anna M. Upton ; Dali Yin ; Zhenkun Ma ; Haihong Huang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8409-8417
• 全文大小：340K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

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 渭g/mL and low cytotoxicity with IC₅₀ values greater than 64 渭g/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.