Analysis of b-amino alcohols as inhibitors of the potential anti-tubercular target N-acetyltransferase Elizabeth Fullam a , Areej Abuhammad a , David L. Wilson b , Matthew C. Anderton a , Steve G. Davies b , Angela J. Russell a,b , Edith Sim a,⇑ a Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK b Department of Chemistry, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK article info Article history: Received 17 November 2010 Revised 14 December 2010 Accepted 18 December 2010 Available online 24 December 2010 Keywords: Tuberculosis Arylamine N-acetyltransferase b-Amino alcohols Enzyme inhibition Drug discovery abstract The synthesis and inhibitory potencies of a novel series of b-amino alcohols, based on the hit-compound 3-[3 0 -(4 00 -cyclopent-2 000 -en-1 000 -ylphenoxy)-2 0 -hydroxypropyl]-5,5 dimethylimidazolidine-2,4-dione as specific inhibitors of mycobacterial N-acetyltransferase (NAT) enzymes are reported. Effects of synthes- ised compounds on growth of Mycobacterium tuberculosis have been determined. Ó 2010 Elsevier Ltd. All rights reserved. Tuberculosis (TB) remains one of the leading causes of death from a single infectious disease worldwide each year. In 2009 the World Health Organisation (WHO) reported 1.7 million people died from TB, equal to 4700 deaths a day, (http://www.who.int/ tb/publications/global_report/2010/) and also reported 9.4 million new cases of TB in the same year. The increase in prevalence of HIV and the emergence of multi-drug resistant (MDR) and extreme drug resistant strains (XDR) means that new drugs are urgently re- quired to prevent a potential pandemic. 1,2 The arylamine N-acetyltransferase (NAT) enzyme has been identified in a number of eukaryotic and prokaryotic species including Mycobacterium tuberculosis, the causative agent of TB and has been identified as a potential new target for the treatment of tuberculosis. When the gene was deleted from Mycobacterium bovis BCG (Dnat) the resulting knockout organism was found to have low levels of mycolic acids and an alteration in the cell wall architecture. 3 The Dnat mutant strain was found to have increased sensitivity to the antibiotics hygromycin and gentamycin that have previously been shown to have little effect on wild-type M. bovis BCG and M. tuberculosis. Importantly these Dnat mutant strains were found to be more susceptible to intracellular killing within mouse macrophages. 3 NAT enzymes utilise the donor cofactor acetyl coenzyme A to acetylate a broad range of substrates including arylamines, N-aryl- hydroxyamines and aryl hydrazines 4 and acyl hydrazides including isoniazid, 5 which is one of the front-line treatments for tuberculo- sis. The crystal structures of NAT enzymes from a number of spe- cies have been solved, including Salmonella typhimurium, 6 Pseudomonas aeruginosa, 7 Nocardia farcinica, 8 human NAT2 9 and the mycobacterial species Mycobacterium smegmatis 10 and Myco- bacterium marinum. 11 All NAT enzymes are found to have very sim- ilar 3-dimensional structures and consist of three distinct domains with the active site containing a catalytic triad formed from a cys- teine, a histidine and an aspartate residue. Recently the cofactor binding site has been identified in human NAT2 9 and M. marinum 11 and found to differ between mammalian and bacterial species. 11 In order to further understand and investigate the role of NAT as an essential target within mycobacteria, small molecule inhibitors of NAT enzymes are required so that a chemical genomic approach can be undertaken to complement the genetic studies which had been previously carried out on Dnat strains of M. bovis BCG 3 and M. smegmatis. 12 Therefore, an in-house library of 5000 selected commercial compounds were screened for in vitro enzymic inhibi- tion against a panel of prokaryotic and eukaryotic NAT en- zymes. 13,14 A smaller manual screen had been previously carried out and been successful in identifying inhibitors of prokaryotic NAT enzymes. 15 From the larger, automated high-throughput screen, six compounds were identified as specific inhibitors of the prokaryotic NAT enzymes with these compounds displaying no inhibitory effect on the eukaryotic enzymes also screened. 13 One of the compounds identified from the more extensive screen 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.12.099 ⇑ Corresponding author. Tel.: +44 1865 271884; fax: +44 1865 271853. E-mail address: edith.sim@pharm.ox.ac.uk (E. Sim). Bioorganic & Medicinal Chemistry Letters 21 (2011) 1185–1190 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl