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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-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

    Bhakta, Sanjib (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-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. 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 anti-tubercular drugs BM212 1 and SQ109 2 that 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 multi-drug 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) towards the whole-cell drug efflux pump activity of mycobacteria, and thus turning to be promising multi-drug resistance reversal agents.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): Tuberculosis, MDR-TB, Antimicrobial resistance, BM212, SQ109, efflux pump, pyrrole, HT-SPOTi, common feature hypothesis generation approach
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Sanjib Bhakta
    Date Deposited: 21 Apr 2016 09:58
    Last Modified: 30 Jun 2020 23:35
    URI: http://eprints.bbk.ac.uk/id/eprint/14902

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