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

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

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Received: 26 February 2014; in revised form: 31 March 2014 / Accepted: 2 April 2014 / Published: 9 April 2014
(This article belongs to the Section Medicinal Chemistry)
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.
Abstract: 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
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MDPI and ACS Style

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.

AMA Style

Zhang D, Liu Y, Zhang C, Zhang H, Wang B, Xu J, Fu L, Yin D, Cooper CB, Ma Z, Lu Y, Huang H. Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents. Molecules. 2014; 19(4):4380-4394.

Chicago/Turabian Style

Zhang, Dongfeng; Liu, Yang; Zhang, Chunlin; Zhang, Hao; Wang, Bin; Xu, Jian; Fu, Lei; Yin, Dali; Cooper, Christopher B.; Ma, Zhenkun; Lu, Yu; Huang, Haihong. 2014. "Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents." Molecules 19, no. 4: 4380-4394.

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