ANTI-FOLATE ANTIMALARIALS WITH DUAL-BINDING MODES AND THEIR PREPARATION

摘要

The present invention is anti-folate antimalarials with dual-binding modes of the general formula (I) [refer to structure in the abstract] wherein R1 and R2 which may be the same or different are independently selected from methyl or ethyl or alkylphenyl, R3 is independently hydrogen, halide, lower alkyl substituted with ester, carboxylic, amide, and ether. Linker is X(CH2)nY wherein X and Y which may be the same or different are independently selected from oxygen, carbon, nitrogen, substituted phenyl where n is an intege from 1 to 2-6, or pharmaceutically acceptable salts therefore. The anti-folate antimalarials with dual-binding modes act as novel inhibitors with good inhibition constants against wild-type, double (C59R+SIOSN), triple (N51+C59R+SIOSN, C59R+S 1 OSN+I164L), and quadruple (N51+C59R+S108N+I164L) mutant enzymes. The compounds are also effective against wild type (Tm4/S.2) and mutants (K1CB1, W2, Csl-2 and V1/S) malaria parasites.