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Exploration of piperidinols as potential antitubercular agents
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Abuhammad, Areej, Fullam, Elizabeth, Bhakta, Sanjib, Russell, Angela, Morris, Garrett, Finn, Paul and Sim, Edith (2014) Exploration of piperidinols as potential antitubercular agents. Molecules, Volume 19 (Number 10). pp. 16274-16290. doi:10.3390/molecules191016274 ISSN 1420-3049.
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Official URL: http://dx.doi.org/10.3390/molecules191016274
Abstract
Novel drugs to treat tuberculosis are required and the identification of potential targets is important. Piperidinols have been identified as potential antimycobacterial agents (MIC < 5 μg/mL), which also inhibit mycobacterial arylamine N-acetyltransferase (NAT), an enzyme essential for mycobacterial survival inside macrophages. The NAT inhibition involves a prodrug-like mechanism in which activation leads to the formation of bioactive phenyl vinyl ketone (PVK). The PVK fragment selectively forms an adduct with the cysteine residue in the active site. Time dependent inhibition of the NAT enzyme from Mycobacterium marinum (M. marinum) demonstrates a covalent binding mechanism for all inhibitory piperidinol analogues. The structure activity relationship highlights the importance of halide substitution on the piperidinol benzene ring. The structures of the NAT enzymes from M. marinum and M. tuberculosis, although 74% identical, have different residues in their active site clefts and allow the effects of amino acid substitutions to be assessed in understanding inhibitory potency. In addition, we have used the piperidinol 3-dimensional shape and electrostatic properties to identify two additional distinct chemical scaffolds as inhibitors of NAT. While one of the scaffolds has anti-tubercular activity, both inhibit NAT but through a non-covalent mechanism.
| Item Type: | Journal Article | ||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
| Library of Congress Subject Headings (LCSH): | Tuberculosis , Tuberculosis -- Treatment, Piperidones, Antitubercular agents | ||||||||
| Journal or Publication Title: | Molecules | ||||||||
| Publisher: | M D P I AG | ||||||||
| ISSN: | 1420-3049 | ||||||||
| Official Date: | 10 October 2014 | ||||||||
| Dates: |
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| Volume: | Volume 19 | ||||||||
| Number: | Number 10 | ||||||||
| Page Range: | pp. 16274-16290 | ||||||||
| DOI: | 10.3390/molecules191016274 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||
| Date of first compliant deposit: | 28 December 2015 | ||||||||
| Date of first compliant Open Access: | 28 December 2015 | ||||||||
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