Molecular Docking Studies, Synthesis and Biological Evaluation of Substituted Pyrimidine-2,4-diamines as Inhibitors of Plasmodium falciparum Dihydrofolate Reductase

Abstract

A series of 5-[(phenethylamino)methyl]pyrimidine-2,4-diamines were assessed in silico as potential inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR), synthesised and tested for inhibitory activity against PfDHFR in vitro. The compounds displayed promising inhibitory activity against both wild-type (K_i 1.3-243 nM) and quadruple mutant (K_i 13-208 nM) PfDHFR in the biochemical enzyme assay, but were less potent in the whole-cell P. falciparum assay (IC₅₀ (TM4/8.2) 0.4-28 μM; IC₅₀ (V1S) 3.7-54 μM). Further investigation into the pharmacokinetic properties of these compounds may guide the development of more potent analogues.

Keywords: Plasmodium falciparum; biological activity; computational chemistry; dihydrofolate reductase; nitrogen heterocycles.