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Citation

BibTex format

@article{Rackham:2014:10.1021/jm500066b,
author = {Rackham, MD and Brannigan, JA and Rangachari, K and Meister, S and Wilkinson, AJ and Holder, AA and Leatherbarrow, RJ and Tate, EW},
doi = {10.1021/jm500066b},
journal = {Journal of Medicinal Chemistry},
pages = {2773--2788},
title = {Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)},
url = {http://dx.doi.org/10.1021/jm500066b},
volume = {57},
year = {2014}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasiticinfections 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 anddisplays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of apreviously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of lessthan 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavyatoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage formsof the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool forfurther optimization.
AU  - Rackham,MD
AU  - Brannigan,JA
AU  - Rangachari,K
AU  - Meister,S
AU  - Wilkinson,AJ
AU  - Holder,AA
AU  - Leatherbarrow,RJ
AU  - Tate,EW
DO  - 10.1021/jm500066b
EP  - 2788
PY  - 2014///
SN  - 0022-2623
SP  - 2773
TI  - Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)
T2  - Journal of Medicinal Chemistry
UR  - http://dx.doi.org/10.1021/jm500066b
UR  - http://hdl.handle.net/10044/1/26923
VL  - 57
ER  -
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Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821