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

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...

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Bibliographic Details
Published in:ChemMedChem 2022-11, Vol.17 (22), p.e202200421-n/a
Main Authors: Seanego, Tswene D., Chavalala, Hlamulo E., Henning, Hendrik H., Koning, Charles B., Hoppe, Heinrich C., Ojo, Kayode K., Rousseau, Amanda L.
Format: Article
Language:English
Subjects:
Amines
Antimalarials - pharmacology
biological activity
calcium-dependent protein kinases
nitrogen heterocycles
Plasmodium falciparum
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Protein Kinase Inhibitors - pharmacology
Protein Kinases - metabolism
Pyrimidines - pharmacology
pyrrolo[2,3-d]pyrimidine
Structure-Activity Relationship
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Summary: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 (IC50=0.210–0.530 μM), or PfCDPK1 (IC50=0.589 μM). These data will enable optimisation of the molecular model to better predict inhibitory activity against PfCDPK4. Hitting malaria where it hurts: Pyrrolo[2,3‐d]pyrimidines have been designed as potential inhibitors targeting Plasmodium falciparum calcium‐dependent protein kinase 4 (PfCDPK4) using molecular modelling. Compounds displaying good binding interactions in silico were synthesised and assessed for inhibitory activity against PfCDPK4 and PfCDPK1, with several compounds displaying promising inhibitory activity against either PfCDPK4 (IC50=0.210–0.530 μM), or PfCDPK1 (IC50=0.589 μM).
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202200421