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Molecules 2014, 19(4), 4380-4394; doi:10.3390/molecules19044380

Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents

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1 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 2 Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, China 3 Global Alliance for TB Drug Development, 40 Wall Street, New York, NY 10005, USA
* Authors to whom correspondence should be addressed.
Received: 26 February 2014 / Revised: 31 March 2014 / Accepted: 2 April 2014 / Published: 9 April 2014
(This article belongs to the Section Medicinal Chemistry)
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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.
Keywords: clofazimine; antituberculosis activity; 2-methoxypyridylamino-substituted riminophenazines; skin discoloration clofazimine; antituberculosis activity; 2-methoxypyridylamino-substituted riminophenazines; skin discoloration
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Zhang, D.; Liu, Y.; Zhang, C.; Zhang, H.; Wang, B.; Xu, J.; Fu, L.; Yin, D.; Cooper, C.B.; Ma, Z.; Lu, Y.; Huang, H. Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents. Molecules 2014, 19, 4380-4394.

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