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Title: Inhibitors of Multiple Mutants of Plasmodium falciparum Dihydrofolate Reductase and Their Antimalarial Activities
Authors: Sumalee Kamchonwongpaisan
Rachel Quarrell
Netnapa Charoensetakul
Rachel Ponsinet
Tirayut Vilaivan
Jarunee Vanichtanankul
Bongkoch Tarnchompoo
Worachart Sirawaraporn
Gordon Lowe
Yongyuth Yuthavong
Thailand National Center for Genetic Engineering and Biotechnology
Chulalongkorn University
Mahidol University
University of Oxford
Keywords: Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 29-Jan-2004
Citation: Journal of Medicinal Chemistry. Vol.47, No.3 (2004), 673-680
Abstract: Novel 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.
ISSN: 00222623
Appears in Collections:Scopus 2001-2005

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