Target guided synthesis of 5-benzyl-2, 4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from …

…, C Intaraudom, S Kamchonwongpaisan…

Index: Sirichaiwat, Chawanee; Intaraudom, Chakapong; Kamchonwongpaisan, Sumalee; Vanichtanankul, Jarunee; Thebtaranonth, Yodhathai; Yuthavong, Yongyuth Journal of Medicinal Chemistry, 2004 , vol. 47, # 2 p. 345 - 354

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Citation Number: 64

Abstract

The resistance to pyrimethamine (PYR) of Plasmodium falciparum arising from mutation at position 108 of dihydrofolate reductase (pfDHFR) from serine to asparagine (S108N) is due to steric interaction between the bulky side chain of N108 and Cl atom of the 5-p-Cl aryl group of PYR, which consequently resulted in the reduction in binding affinity between the enzyme and inhibitor. Molecular modeling suggested that the flexible antifolate, such as ...