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 inâ vitro. The compounds displayed promising inhibitory activity against both wild-type (Ki 1.3-243â nM) and quadruple mutant (Ki 13-208â nM) PfDHFR in the biochemical enzyme assay, but were less potent in the whole-cell P. falciparum assay (IC50 (TM4/8.2) 0.4-28â µM; IC50 (V1S) 3.7-54â µM). Further investigation into the pharmacokinetic properties of these compounds may guide the development of more potent analogues.
Subject(s)
Antimalarials , Folic Acid Antagonists , Tetrahydrofolate Dehydrogenase/chemistry , Plasmodium falciparum , Molecular Docking Simulation , Folic Acid Antagonists/pharmacology , Antimalarials/pharmacology , Antimalarials/chemistry , Diamines/pharmacology , Pyrimidines/pharmacologyABSTRACT
A series of pyrrolo[2,3-d]pyrimidines were designed in silico as potential bumped kinase inhibitors targeting P. falciparum calcium dependent protein kinase 4 (PfCDPK4), with the potential to inhibit PfCDPK1 based on earlier studies of the two kinases. A small series of these compounds were prepared and assessed for inhibitory activity against PfCDPK4 and PfCDPK1 inâ vitro. Four of the compounds displayed promising inhibitory activity against either PfCDPK4 (IC50 =0.210-0.530â µM), or PfCDPK1 (IC50 =0.589â µM). These data will enable optimisation of the molecular model to better predict inhibitory activity against PfCDPK4.