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dc.contributor.authorSumalee Kamchonwongpaisanen_US
dc.contributor.authorRachel Quarrellen_US
dc.contributor.authorNetnapa Charoensetakulen_US
dc.contributor.authorRachel Ponsineten_US
dc.contributor.authorTirayut Vilaivanen_US
dc.contributor.authorJarunee Vanichtanankulen_US
dc.contributor.authorBongkoch Tarnchompooen_US
dc.contributor.authorWorachart Sirawarapornen_US
dc.contributor.authorGordon Loween_US
dc.contributor.authorYongyuth Yuthavongen_US
dc.contributor.otherThailand National Center for Genetic Engineering and Biotechnologyen_US
dc.contributor.otherChulalongkorn Universityen_US
dc.contributor.otherMahidol Universityen_US
dc.contributor.otherUniversity of Oxforden_US
dc.identifier.citationJournal of Medicinal Chemistry. Vol.47, No.3 (2004), 673-680en_US
dc.description.abstractNovel analogues of pyrimethamine (Pyr) and cycloguanil (Cyc) have been synthesized and tested as inhibitors of Plasmodium falciparum dihydrofolate reductase carrying triple (N51I+C59R+S108N, C59R+S108N+I164L) and quadruple (N51I+C59R+S108N+I164L) mutations responsible for antifolate resistance. The inhibitors were designed to avoid steric clash of the p-Cl group of the inhibitors with the side chain of Asn108, augmented by additional mutations of the resistant mutants. Cycloguanil derivatives were also designed to avoid steric clash with the side chain of Val16 in the A16V+S108T mutant. Many compounds have inhibition constants (Ki) at the low nanomolar level against the mutant enzymes and a number have good antimalarial activities against resistant P. falciparum parasites bearing multiple mutations in the S108N series and A16V+S108T mutant enzymes. These compounds in the Pyr and Cyc series exhibit low and moderate cytotoxicity to nontumor (Vero) and tumor (KB, BC) cell lines. Some of these inhibitors are therefore potential candidates for further development as antimalarials.en_US
dc.rightsMahidol Universityen_US
dc.subjectBiochemistry, Genetics and Molecular Biologyen_US
dc.subjectPharmacology, Toxicology and Pharmaceuticsen_US
dc.titleInhibitors of Multiple Mutants of Plasmodium falciparum Dihydrofolate Reductase and Their Antimalarial Activitiesen_US
Appears in Collections:Scopus 2001-2005

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