Antimycobacterial Agents. Novel Diarylpyrrole Derivatives of BM212 Endowed with High Activity toward Mycobacterium tuberculosis and Low Cytotoxicity
- 7 July 2006
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 49 (16), 4946-4952
- https://doi.org/10.1021/jm0602662
Abstract
On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or from a structure−activity relationship analysis of many pyrroles previously described by us, we report here the design and synthesis of new analogues of 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212). Various substituents with different substitution patterns were added to both positions 1 and 5 of the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. Biological data showed that, although some nontuberculosis mycobacterial strains were found to be sensitive, MIC values were higher than those found toward MTB. The best compound (1-(4-fluorophenyl)-2-methyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole, 5) possessed a MIC of 0.4 μg/mL (better than BM212 and streptomycin) and a very high protection index (160), better than BM212, isoniazid, and streptomycin (6, 128, and 128, respectively). Finally, molecular modeling studies were performed to rationalize the activity of the new compounds in terms of both superposition onto a pharmacophoric model for antitubercular compounds and their hydrophobic character.Keywords
This publication has 18 references indexed in Scilit:
- Treatment of Active Tuberculosis: Challenges and ProspectsClinics in Chest Medicine, 2005
- Treatment of Latent Tuberculosis Infection: Challenges and ProspectsClinics in Chest Medicine, 2005
- The DOTS Strategy for Controlling the Global Tuberculosis EpidemicClinics in Chest Medicine, 2005
- The Diagnosis of TuberculosisClinics in Chest Medicine, 2005
- Global Epidemiology of TuberculosisClinics in Chest Medicine, 2005
- The global situation of MDR-TBTuberculosis, 2003
- New pyrrole derivatives as antimycobacterial agents analogs of BM212Bioorganic & Medicinal Chemistry Letters, 1999
- Bactericidal Activities of the Pyrrole Derivative BM212 against Multidrug-Resistant and Intramacrophagic Mycobacterium tuberculosis StrainsAntimicrobial Agents and Chemotherapy, 1998
- Mechanisms of latency in Mycobacterium tuberculosisTrends in Microbiology, 1998
- Epidemiology of infection by nontuberculous mycobacteriaClinical Microbiology Reviews, 1996