Abstract
The design, synthesis and biological evaluation of a series of 6-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines is described. These compounds exhibited in vitro antiplasmodial activity in the low nanomolar range against both drug sensitive and drug resistant strains of P. falciparum, with 1-(3-(2,4-dichlorophenoxy)propyl)-6-phenyl-1,6-dihydro-1,3,5-triazine-2,4-diamine hydrochloride identified as the most potent compound from this series against the drug resistant FCR-3 strain (IC50 2.66 nM). The compounds were not toxic to mammalian cells at therapeutic concentrations and were shown to be inhibitors of parasitic DHFR in a biochemical enzyme assay.
Highlights
Malaria continues to pose a health risk to much of the world population despite a dramatic decrease in malaria morbidity over the past 15 years.[1]
The active site was defined at chain A of the DHFR region with the co-factor NADPH bound, in order to assess the comparative binding of the inhibitor molecules at the dihydrofolate binding site
Good activities against the mutant enzyme (Ala16Val+Ser108Thr DHFR) can be explained by the flexibility of the 5-side chain which can avert steric hindrance introduced by the Ser108Thr mutation, while the 6-aryl substituent, in contrast to the 6,6-dimethyl groups of cycloguanil, can avert steric hindrance caused by the Ala16Val mutation
Summary
Malaria continues to pose a health risk to much of the world population despite a dramatic decrease in malaria morbidity over the past 15 years.[1]. The initial series of compounds synthesised (Table 1) were assessed for antimalarial activity in vitro in a whole cell P. falciparum assay against a cycloguanil resistant strain All other compounds of the series bearing flexible linkers of 1, 2 or 3 atoms only showed activity comparable with cycloguanil against the drug resistant P. falciparum strain (IC50 2.12–7.16 μM; cf cycloguanil IC50 14.5 μM in this assay, entry 9 of Table 1).
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