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

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 e...

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Autores principales: Liu, Binna, Liu, Kai, Lu, Yu, Zhang, Dongfeng, Yang, Tianming, Li, Xuan, Ma, Chen, Zheng, Meiqin, Wang, Bin, Zhang, Gang, Wang, Fei, Ma, Zhenkun, Li, Chun, Huang, Haihong, Yin, Dali
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269036/
https://www.ncbi.nlm.nih.gov/pubmed/22510605
http://dx.doi.org/10.3390/molecules17044545
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author Liu, Binna
Liu, Kai
Lu, Yu
Zhang, Dongfeng
Yang, Tianming
Li, Xuan
Ma, Chen
Zheng, Meiqin
Wang, Bin
Zhang, Gang
Wang, Fei
Ma, Zhenkun
Li, Chun
Huang, Haihong
Yin, Dali
author_facet Liu, Binna
Liu, Kai
Lu, Yu
Zhang, Dongfeng
Yang, Tianming
Li, Xuan
Ma, Chen
Zheng, Meiqin
Wang, Bin
Zhang, Gang
Wang, Fei
Ma, Zhenkun
Li, Chun
Huang, Haihong
Yin, Dali
author_sort Liu, Binna
collection PubMed
description 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.
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spelling pubmed-62690362018-12-11 Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis Liu, Binna Liu, Kai Lu, Yu Zhang, Dongfeng Yang, Tianming Li, Xuan Ma, Chen Zheng, Meiqin Wang, Bin Zhang, Gang Wang, Fei Ma, Zhenkun Li, Chun Huang, Haihong Yin, Dali Molecules Article 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. MDPI 2012-04-17 /pmc/articles/PMC6269036/ /pubmed/22510605 http://dx.doi.org/10.3390/molecules17044545 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ 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
Liu, Binna
Liu, Kai
Lu, Yu
Zhang, Dongfeng
Yang, Tianming
Li, Xuan
Ma, Chen
Zheng, Meiqin
Wang, Bin
Zhang, Gang
Wang, Fei
Ma, Zhenkun
Li, Chun
Huang, Haihong
Yin, Dali
Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis
title Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis
title_full Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis
title_fullStr Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis
title_full_unstemmed Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis
title_short Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis
title_sort systematic evaluation of structure-activity relationships of the riminophenazine class and discovery of a c2 pyridylamino series for the treatment of multidrug-resistant tuberculosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269036/
https://www.ncbi.nlm.nih.gov/pubmed/22510605
http://dx.doi.org/10.3390/molecules17044545
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