Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/6722
Title: Design and synthesis of 1-((1,5-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N'-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine (SQ109) pyrrole hybrid derivatives: discovery of potent anti-tubercular agents effective against multi-drug resistant mycobacteria
Authors: Sanjib Bhakta
Nicolò€ Scalacci
Arundhati Maitra
Alistair K Brown
Saiprasad Dasugari
Dimitrios Evangelopoulos
Timothy D McHugh
Parisa N Mortazavi
Alexander Twist
Elena Petricci
Fabrizio Manetti
Daniele Castagnolo
Keywords: Antitubercular agents, hybrid compounds, pyrrole derivatives, BM212, SQ109, Mycobacterium tuberculosis, pharmacophoric model, superposition
Issue Date: 2016
Project: None 
Journal: JOURNAL OF MEDICINAL CHEMISTRY
Abstract: 
Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reversing agents.
Description: 
111554
URI: http://hdl.handle.net/20.500.12779/6722
ISSN: 1520-4804
DOI: 10.1021/acs.jmedchem.6b00031
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