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 (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.

Characterization, crystallization and preliminary X-ray analysis of bifunctional dihydrofolate reductase–thymidylate synthase fromPlasmodium falciparum

“…Pyr30 (also known as SO3) is the m-chloro analogue of pyrimethamine, while Pyr39 is a pyrimethamine derivative without the p-chloro atom and with a 6-n-hexyl group in place of the 6-ethyl group. They both retain binding af®nity to the mutant enzymes and have good antimalarial activities against mutant parasites (Kamchonwongpaisan et al, 2004). The crystal structures of the complexes in comparison with the complex with pyrimethamine (Yuvaniyama et al, 2003) should give insights into development of new effective compounds against resistant parasites.…”

A new protoberberine alkaloid from Meconopsis simplicifolia (D. Don) Walpers with potent antimalarial activity against a multidrug resistant Plasmodium falciparum strain

“…The method described by Trager and Jensen (1976) was used for maintaining the parasites in human red blood cells in RPMI 1640 medium supplemented with 25 mM of HEPES, 0.2% of sodium bicarbonate, and 8% human serum in a 3% carbon dioxide gas incubator maintained H-hypoxanthine incorporation (Desjardins et al, 1979;Kamchonwongpaisan et al, 2004). The inhibitory concentration of the sample was determined from its dose-response curves or by calculation.…”

Alkaloids from the roots of Stemona javanica (Kunth) Engl. (Stemonaceae) and their anti-malarial, acetylcholinesterase inhibitory and cytotoxic activities

“…Compounds 1−4 and protostemonine were tested in vitro against a multidrug resistant K1CB1 strain and a wild type chloroquine and antifolate sensitive TM4/8.2 strain of Plasmodium falciparum using a previously described method (Trager and Jensen, 1976;Wangchuk et al, 2011;Desjardins et al, 1979;Kamchonwongpaisan et al, 2004).…”