Target fishing reveals PfPYK-1 and PfRab6 as potential targets of an antiplasmodial 4-anilino-2-trichloromethylquinazoline hit compound

We present investigations about the mechanism of action of a previously reported 4-anilino-2-trichloromethylquinazoline antiplasmodial hit-compound (Hit A), which did not share a common mechanism of action with established commercial antimalarials and presented a stage-specific effect on the erythrocytic cycle of P. falciparum at 8 < t < 16 h. The target of Hit A was searched by immobilising the molecule on a solid support via a linker and performing affinity chromatography on a plasmodial lysate. Several anchoring positions of the linker (6,7 and 3') and PEG-type linkers were assessed, to obtain a linked-hit molecule displaying in vitro antiplasmodial activity similar to that of unmodified Hit A. This allowed us to identify the PfPYK-1 kinase and the PfRab6 GTP-ase as potential targets of Hit A.PMID:38452406 | DOI:10.1016/j.bmc.2024.117654

Source: Bioorganic and Medicinal Chemistry - March 7, 2024 Category: Chemistry Authors: C Kieffer N Primas S Hutter A Merckx L Reininger S Bach S Ruchaud F Gaillard M Laget D Amrane L Herv é C Castera-Ducros J Renault A Dum ètre S Rault C Doerig P Rathelot P Vanelle N Azas P Verhaeghe Source Type: research