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Molecules 2014, 19(10), 16274-16290;

Exploration of Piperidinols as Potential Antitubercular Agents

Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Queen Rania Street, Amman 11942, Jordan
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK
InhibOx, Oxford Centre for Innovation, New Road, Oxford OX1 1BY, UK
Faculty of Science, Engineering and Computing, Kingston University, Penrhyn Road, Kingston KT1 2EE, UK
Department of Applied Computing, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK
Present address: Department of Biological Science, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK.
Author to whom correspondence should be addressed.
Received: 14 July 2014 / Revised: 9 September 2014 / Accepted: 24 September 2014 / Published: 10 October 2014
(This article belongs to the Special Issue Prodrugs)
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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. View Full-Text
Keywords: tuberculosis; covalent inhibitors; piperidinols; arylamine N-acetyltransferase tuberculosis; covalent inhibitors; piperidinols; arylamine N-acetyltransferase

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Abuhammad, A.; Fullam, E.; Bhakta, S.; Russell, A.J.; Morris, G.M.; Finn, P.W.; Sim, E. Exploration of Piperidinols as Potential Antitubercular Agents. Molecules 2014, 19, 16274-16290.

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