2. Academic Validation
  3. Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis

Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis

  • J Med Chem. 2012 Oct 11;55(19):8409-17. doi: 10.1021/jm300828h.
Dongfeng Zhang 1,  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
Affiliations

Affiliation

  • 1 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.
PMID: 22931472 DOI: 10.1021/jm300828h
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.

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