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

• DOI: 10.1021/jm030165t
• Publication Date: 2004-01-22T11:09:25Z
• Authors: Sumalee Kamchonwo...; Rachel Quarrell; Netnapa Charoense...; Rachel Ponsinet; Tirayut Vilaivan; Jarunee Vanichtan...; Bongkoch Tarnchompoo; Worachart Sirawar...; Gordon Lowe; Yongyuth Yuthavong
• Keywords: 0301 basic medicine; Triazines; Plasmodium falciparum; Drug Resistance; Cell Line; 3. Good health; Antimalarials; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; 03 medical and health sciences; Pyrimethamine; Proguanil; Chlorocebus aethiops; Mutation; Animals; Folic Acid Antagonists; Humans

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.