Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis

Molecules

Binna Liu¹  Kai Liu¹  Yu Lu³  Dongfeng Zhang¹  Tianming Yang¹  Xuan Li¹  Chen Ma¹  Meiqin Zheng³  Bin Wang³  Gang Zhang¹  Fei Wang¹  Zhenkun Ma²  Chun Li¹  Haihong Huang¹ 

[1] State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance 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, China;Global Alliance for TB Drug Development, 40 Wall Street, New York, NY 10005, USA;Beijing Tuberculosis and Thoracic Tumor Research Institute, 97 Ma Chang Street, Beijing 101149, China

关键词: anti-tuberculosis;    MDR-TB;    riminophenazine;    clofazimine;    skin pigmentation;   

DOI  :  10.3390/molecules17044545

来源: mdpi

【 摘 要 】

Clofazimine, a member of the riminophenazine class of drugs, is the cornerstone agent for the treatment of leprosy. This agent is currently being studied in clinical trials for the treatment of multidrug-resistant tuberculosis to address the urgent need for new drugs that can overcome existing and emerging drug resistance. However, the use of clofazimine in tuberculosis treatment is hampered by its high lipophilicity and skin pigmentation side effects. To identify a new generation of riminophenazines that is less lipophilic and skin staining, while maintaining efficacy, we have performed a systematic structure-activity relationship (SAR) investigation by synthesizing a variety of analogs of clofazimine and evaluating their anti-tuberculosis activity. The study reveals that the central tricyclic phenazine system and the pendant aromatic rings are important for anti-tuberculosis activity. However, the phenyl groups attached to the C2 and N5 position of clofazimine can be replaced by a pyridyl group to provide analogs with improved physicochemical properties and pharmacokinetic characteristics. Replacement of the phenyl group attached to the C2 position by a pyridyl group has led to a promising new series of compounds with improved physicochemical properties, improved anti-tuberculosis potency, and reduced pigmentation potential.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.