exploration of piperidinols as potential antitubercular agents

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ID: 231236
2014
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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.
Reference Key
abuhammad2014moleculesexploration Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Areej Abuhammad;Elizabeth Fullam;Sanjib Bhakta;Angela J. Russell;Garrett M. Morris;Paul W. Finn;Edith Sim
Journal Journal of ethnopharmacology
Year 2014
DOI
10.3390/molecules191016274
URL
http://www.mdpi.com/1420-3049/19/10/16274
Keywords
tuberculosis covalent inhibitors

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