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-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

Bhakta, Sanjib, Scalacci, Nicolò, Maitra, Arundhati, Brown, Alistair, Dasugari, Saiprasad, Evangelopoulos, Dimitrios, McHugh, Timothy, Mortazavi, Parisa, Twist, Alexander, Petricci, Elena, Manetti, Fabrizio and Castagnolo, Daniele (2016) 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-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria. Journal of Medicinal Chemistry, 59 (6). pp. 2780-2793. ISSN 0022-2623

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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.

Item Type:	Article
Subjects:	C700 Molecular Biology, Biophysics and Biochemistry F100 Chemistry
Department:	Faculties > Health and Life Sciences > Applied Sciences
Depositing User:	Ay Okpokam
Date Deposited:	25 Apr 2016 11:11
Last Modified:	12 May 2022 15:49
URI:	http://nrl.northumbria.ac.uk/id/eprint/26636

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