title: Exploration of piperidinols as potential antitubercular agents.
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.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Areej
authors.initials: A
authors.lastname: Abuhammad
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fullam
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Bhakta
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Russell
authors.affiliation: InhibOx, Oxford Centre for Innovation, New Road, Oxford OX1 1BY, UK.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Morris
authors.affiliation: InhibOx, Oxford Centre for Innovation, New Road, Oxford OX1 1BY, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Finn
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. E.Sim@kingston.ac.uk.
authors.forename: Edith
authors.initials: E
authors.lastname: Sim
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D006801:Humans; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D000995:Antitubercular Agents; D010880:Piperidines; D000123:Acetyltransferases