Development of benzophenone-based farnesyltransferase inhibitors as novel antimalarials.

The development of farnesyltransferase inhibitors directed against Plasmodium falciparum is a strategy towards new drugs against malaria. Previously, we described benzophenone-based farnesyltransferase inhibitors with high in vitro antimalarial activity but no in vivo activity. Through the introduction of a methylpiperazinyl moiety, farnesyltransferase inhibitors with in vivo antimalarial activity were obtained. Subsequently, a structure-based design approach was chosen to further improve the antimalarial activity of this type of inhibitor. As no crystal structure of the farnesyltransferase of the target organism is available, homology modeling was used to reveal differences between the active sites of the rat/human and the P. falciparum farnesyltransferase. Based on flexible docking data, the piperazinyl moiety was replaced by a N,N,N'-trimethylethylenediamine moiety. This resulted in an inhibitor with significantly improved in vitro and in vivo antimalarial activity. Furthermore, this inhibitor displayed a notable increase in selectivity towards malaria parasites relative to human cells.