Inhibitors of Multiple Mutants of Plasmodium falciparum Dihydrofolate Reductase and Their Antimalarial Activities

• Published in: Journal of medicinal chemistry 2004-01, Vol.47 (3), p.673-680
• Main Authors: KAMCHONWONGPAISAN, Sumalee, QUARRELL, Rachel, CHAROENSETAKUL, Netnapa, PONSINET, Rachel, VILAIVAN, Tirayut, VANICHTANANKUL, Jarunee, TARNCHOMPOO, Bongkoch, SIRAWARAPORN, Worachart, LOWE, Gordon, YUTHAVONG, Yongyuth
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Antimalarials - toxicity; Antiparasitic agents; Biological and medical sciences; Cell Line; Cercopithecus aethiops; Drug Resistance; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - pharmacology; Folic Acid Antagonists - toxicity; Humans; Medical sciences; Mutation; Pharmacology. Drug treatments; Plasmodium falciparum - enzymology; Proguanil; Pyrimethamine - analogs & derivatives; Pyrimethamine - chemical synthesis; Pyrimethamine - pharmacology; Pyrimethamine - toxicity; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase - genetics; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030165t

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 (K(i)) 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.