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Rackham, MD, Brannigan, JA, Rangachari, K, Meister, S, Wilkinson, AJ, Holder, AA, Leatherbarrow, RJ and Tate, EW (2014) Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP). Journal of Medicinal Chemistry, 57 (6). pp. 2773-2778. ISSN 0022-2623
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Design and Synthesis of High Affinity Inhibitors of Plasmodium.pdf - Published Version Available under License Creative Commons Attribution. Download (3MB) | Preview |
Abstract
N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.
| Item Type: | Article |
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| Uncontrolled Keywords: | 0304 Medicinal And Biomolecular Chemistry, 1115 Pharmacology And Pharmaceutical Sciences, 0305 Organic Chemistry |
| Subjects: | Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Vice-Chancellor's Office |
| Publisher: | American Chemical Society |
| Related URLs: | |
| Date Deposited: | 19 Jun 2018 11:36 |
| Last Modified: | 04 Sep 2021 02:37 |
| DOI or ID number: | 10.1021/jm500066b |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/8856 |
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