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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, S.; Scalacci, N.; Maitra, A.; Brown, A.K.; Dasugari, S.; Evangelopoulos, D.; McHugh, T.D.; Mortazavi, P.N.; Twist, A.; Petricci, E.; Manetti, F.; Castagnolo, D.

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 Thumbnail


Authors

S. Bhakta

N. Scalacci

A. Maitra

A.K. Brown

S. Dasugari

D. Evangelopoulos

T.D. McHugh

P.N. Mortazavi

A. Twist

E. Petricci

F. Manetti

D. Castagnolo



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.

Citation

Bhakta, S., Scalacci, N., Maitra, A., Brown, A., Dasugari, S., Evangelopoulos, D., …Castagnolo, D. (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), 2780-2790. https://doi.org/10.1021/acs.jmedchem.6b00031

Journal Article Type Article
Acceptance Date Feb 23, 2016
Online Publication Date Feb 23, 2016
Publication Date Mar 24, 2016
Deposit Date Mar 16, 2016
Publicly Available Date Feb 23, 2017
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 59
Issue 6
Pages 2780-2790
DOI https://doi.org/10.1021/acs.jmedchem.6b00031

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Copyright Statement
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.jmedchem.6b00031.




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