Two series of substituted pyrimidine-2,4-diamines with a flexible side chain at either the 5-or 6-position of the pyrimdine ring were designed as potential inhibitors of P. falciparum dihydrofolate reductase (DHFR). The compounds were synthesised and evaluated for antiplasmodial activity in vitro against a cycloguanil-resistant strain of the P. falciparum parasite. 5-(3-(3,5-Dichlorophenoxy)propyl)-6-phenylpyrimidine-2,4-diamine was identified as the most promising compound (IC 50 0.86 µM). In general, pyrimidine-2,4-diamines substituted at the 5-position of the pyrimidine ring showed better antiplasmodial activity (IC 50 0.86 -26.55 µM ) than those bearing a modified side chain at the 6-position of the pyrimidine ring (IC 50 4.46 -83.45 µM).
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 (Ki 1.3–243 nM) and quadruple mutant (Ki 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.
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 in vitro. Four of the compounds displayed promising inhibitory activity against either PfCDPK4 (IC 50 = 0.210-0.530 μM), or PfCDPK1 (IC 50 = 0.589 μM). These data will enable optimisation of the molecular model to better predict inhibitory activity against PfCDPK4.
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