Publication: Inhibitors of Multiple Mutants of Plasmodium falciparum Dihydrofolate Reductase and Their Antimalarial Activities
Issued Date
2004-01-29
Resource Type
ISSN
00222623
Other identifier(s)
2-s2.0-9144272211
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Medicinal Chemistry. Vol.47, No.3 (2004), 673-680
Suggested Citation
Sumalee Kamchonwongpaisan, Rachel Quarrell, Netnapa Charoensetakul, Rachel Ponsinet, Tirayut Vilaivan, Jarunee Vanichtanankul, Bongkoch Tarnchompoo, Worachart Sirawaraporn, Gordon Lowe, Yongyuth Yuthavong Inhibitors of Multiple Mutants of Plasmodium falciparum Dihydrofolate Reductase and Their Antimalarial Activities. Journal of Medicinal Chemistry. Vol.47, No.3 (2004), 673-680. doi:10.1021/jm030165t Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/21231
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Title
Inhibitors of Multiple Mutants of Plasmodium falciparum Dihydrofolate Reductase and Their Antimalarial Activities
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.