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Title: Rational drug design approach for overcoming drug resistance: Application to pyrimethamine resistance in malaria
Authors: James H. McKie
Kenneth T. Douglas
Cecil Chan
Simon A. Roser
Robert Yates
Martin Read
John E. Hyde
Michael J. Dascombe
Yongyuth Yuthavong
Worachart Sirawaraporn
University of Manchester
University of Manchester School of Medicine
Thailand National Science and Technology Development Agency
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 23-Apr-1998
Citation: Journal of Medicinal Chemistry. Vol.41, No.9 (1998), 1367-1370
Abstract: Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (K(i) 1.5 nM) with purified recombinant DHFR from P. falciparum, the K(i) value of the m- methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the K(i) values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with K(i) 0.30 nM) and the doubly mutant (C59R + S108N) purified enzyme (with K(i) 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 μM for the m-methoxy and 0.6 μM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 μM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.
ISSN: 00222623
Appears in Collections:Scopus 1991-2000

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