Next Article in Journal
Unraveling the Photocatalytic Mechanisms on TiO2 Surfaces Using the Oxygen-18 Isotopic Label Technique
Next Article in Special Issue
Modern Prodrug Design for Targeted Oral Drug Delivery
Previous Article in Journal
Photoregeneration of Trimethylsilyl Cellulose as a Tool for Microstructuring Ultrathin Cellulose Supports
Previous Article in Special Issue
Synthesis, Leishmanicidal and Cytotoxic Activity of Triclosan-Chalcone, Triclosan-Chromone and Triclosan-Coumarin Hybrids
Article Menu
Issue 10 (October) cover image

Export Article

Open AccessArticle
Molecules 2014, 19(10), 16274-16290; doi:10.3390/molecules191016274

Exploration of Piperidinols as Potential Antitubercular Agents

1
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK
2
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Queen Rania Street, Amman 11942, Jordan
3
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
4
School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK
5
InhibOx, Oxford Centre for Innovation, New Road, Oxford OX1 1BY, UK
6
Faculty of Science, Engineering and Computing, Kingston University, Penrhyn Road, Kingston KT1 2EE, UK
7
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)
View Full-Text   |   Download PDF [1074 KB, uploaded 10 October 2014]   |  

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. View Full-Text
Keywords: tuberculosis; covalent inhibitors; piperidinols; arylamine N-acetyltransferase tuberculosis; covalent inhibitors; piperidinols; arylamine N-acetyltransferase
Figures

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).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top