Next Article in Journal
A Support Vector Machine Classification Model for Benzo[c]phenathridine Analogues with Topoisomerase-I Inhibitory Activity
Previous Article in Journal
Large-Scale Solvent-Free Chlorination of Hydroxy-Pyrimidines, -Pyridines, -Pyrazines and -Amides Using Equimolar POCl3
Molecules 2012, 17(4), 4545-4559; doi:10.3390/molecules17044545
Article

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

1, 1, 2, 1, 1, 1, 1, 2, 2, 1, 1, 3,* , 1, 1 and 1,*
Received: 9 March 2012; in revised form: 9 April 2012 / Accepted: 10 April 2012 / Published: 17 April 2012
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [321 KB, uploaded 18 June 2014]   |   Browse Figures
Abstract: 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.
Keywords: anti-tuberculosis; MDR-TB; riminophenazine; clofazimine; skin pigmentation anti-tuberculosis; MDR-TB; riminophenazine; clofazimine; skin pigmentation
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.

Export to BibTeX |
EndNote


MDPI and ACS Style

Liu, B.; Liu, K.; Lu, Y.; Zhang, D.; Yang, T.; Li, X.; Ma, C.; Zheng, M.; Wang, B.; Zhang, G.; Wang, F.; Ma, Z.; Li, C.; Huang, H.; Yin, D. Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis. Molecules 2012, 17, 4545-4559.

AMA Style

Liu B, Liu K, Lu Y, Zhang D, Yang T, Li X, Ma C, Zheng M, Wang B, Zhang G, Wang F, Ma Z, Li C, Huang H, Yin D. Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis. Molecules. 2012; 17(4):4545-4559.

Chicago/Turabian Style

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. 2012. "Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis." Molecules 17, no. 4: 4545-4559.


Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert