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: Dihydrofolate reductase; Antifolate

Novel analogues of pyrimethamine (Pyr) and cycloguanil (Cyc) have been synthesized tested as inhibitors Plasmodium falciparum dihydrofolate reductase carrying triple (N51I+C59R+S108N, C59R+S108N+I164L) quadruple (N51I+C59R+S108N+I164L) mutations responsible for antifolate resistance. The were designed to avoid steric clash the p-Cl group with side chain Asn108, augmented by additional resistant mutants. Cycloguanil derivatives also Val16 in A16V+S108T mutant. Many compounds inhibition constants (Ki) at low nanomolar level against mutant enzymes a number good antimalarial activities P. parasites bearing multiple S108N series enzymes. These Pyr Cyc exhibit moderate cytotoxicity nontumor (Vero) tumor (KB, BC) cell lines. Some these are therefore potential candidates further development antimalarials.