7H‐Pyrrolo[2,3‐d]pyrimidine‐4‐amines as Potential Inhibitors of Plasmodium falciparum Calcium‐Dependent Protein Kinases

Abstract

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.

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…Seanego and co-workers have identified 7H-pyrrolo[2,3d]pyrimidine-4-amine (97) with IC 50 of 14.2 μM against Pf3D7 strains inhibiting calcium-dependent protein kinase (a target involved in maturation of gametocytes) PfCDPK1 (> 2 μM) and PfCDPK4 (0.53 μM) without any cytotoxicity against mammalian cell lines. [111] Bailey and his co-workers have identified triazolopyrimidine (98) with IC 50 of 0.06 μM through the high throughput screening of the Janssen Jumpstarter library. [112] The evaluation of the activity of 98 against PfDd2 and P. knowlesi revealed its EC 50 of 0.07 and 1.18, respectively.…”