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|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
Alistair K Brown
Timothy D McHugh
Parisa N Mortazavi
|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.
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