Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271099/
https://www.ncbi.nlm.nih.gov/pubmed/24722591
http://dx.doi.org/10.3390/molecules19044380
_version_ 1783376850546851840
author 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
author_facet 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
author_sort Zhang, Dongfeng
collection PubMed
description 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 IC(50) 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.
format Online
Article
Text
id pubmed-6271099
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-62710992019-01-02 Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents 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 Molecules Article 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 IC(50) 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. MDPI 2014-04-09 /pmc/articles/PMC6271099/ /pubmed/24722591 http://dx.doi.org/10.3390/molecules19044380 Text en © 2014 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
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
Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents
title Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents
title_full Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents
title_fullStr Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents
title_full_unstemmed Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents
title_short Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents
title_sort synthesis and biological evaluation of novel 2-methoxypyridylamino-substituted riminophenazine derivatives as antituberculosis agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271099/
https://www.ncbi.nlm.nih.gov/pubmed/24722591
http://dx.doi.org/10.3390/molecules19044380
work_keys_str_mv AT zhangdongfeng synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT liuyang synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT zhangchunlin synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT zhanghao synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT wangbin synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT xujian synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT fulei synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT yindali synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT cooperchristopherb synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT mazhenkun synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT luyu synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents
AT huanghaihong synthesisandbiologicalevaluationofnovel2methoxypyridylaminosubstitutedriminophenazinederivativesasantituberculosisagents