Synthesis and biological evaluation of novel 2-methoxypyridylamino-substituted riminophenazine derivatives as antituberculosis agents.
Clofazimine, a member of the riminophenazine class, is one of the few antibiotics that are still active against multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). However, the clinical utility of this agent is limited by its undesirable physicochemical properties and skin pigmentation potential. With the goal of maintaining potent antituberculosis activity while improving physicochemical properties and lowering skin pigmentation potential, a series of novel riminophenazine derivatives containing a 2-methoxypyridylamino substituent at the C-2 position of the phenazine nucleus were designed and synthesized. These compounds were evaluated for antituberculosis activity against M. tuberculosis H37Rv and screened for cytotoxicity. Riminophenazines bearing a 3-halogen- or 3,4-dihalogen-substituted phenyl group at the N-5 position exhibited potent antituberculosis activity, with MICs ranging from 0.25~0.01 μg/mL. The 3,4-dihalogen- substituted compounds displayed low cytotoxicity, with IC50 values greater than 64 μg/mL. Among these riminophenazines, compound 15 exhibited equivalent in vivo efficacy against M. tuberculosis infection and reduced skin discoloration potential in an experimental mouse infection model as compared to clofazimine. Compound 15, as compared to clofazimine, also demonstrated improved physicochemical properties and pharmacokinetic profiles with a short half-life and less drug tissue accumulation. This compound is being evaluated as a potential drug candidate for the treatment of multidrug resistant tuberculosis.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China. zdf@imm.ac.cn.
Dongfeng
D
Zhang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China. liuyang3923@163.com.
Yang
Y
Liu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China. chunlin.zhang@hotmail.com.
Chunlin
C
Zhang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China. hubert365@163.com.
Hao
H
Zhang
Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, China. binbin69823233@126.com.
Bin
B
Wang
Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, China. xujian4614@gmail.com.
Jian
J
Xu
Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, China. fl2000x@163.com.
Lei
L
Fu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China. yindali@imm.ac.cn.
Dali
D
Yin
Global Alliance for TB Drug Development, 40 Wall Street, New York, NY 10005, USA. christopher.cooper@tballiance.org.
Christopher B
CB
Cooper
Global Alliance for TB Drug Development, 40 Wall Street, New York, NY 10005, USA. zhenkun.ma@tennorx.com.
Zhenkun
Z
Ma
Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, China. luyu4876@hotmail.com.
Yu
Y
Lu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China. joyce@imm.ac.cn.
Haihong
H
Huang
D000284:Administration, Oral; D000631:Aminopyridines / Q000737:chemistry*; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002991:Clofazimine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D006207:Half-Life; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
D000631:Aminopyridines; D000995:Antitubercular Agents; D002991:Clofazimine