In Vitro And In Vivo Antimalarial Activity Of Peptidomimetic Protein Farnesyltransferase Inhibitors With Improved Membrane Permeability

A series of ester derivatives of 17 with increased lipophilicity were synthesized and tested against P. falciparum in red blood cells, where the benzyl ester derivative 16 exhibited the best inhibition activity (ED 50 = 150 nM). Compound 16 showed in vivo antimalarial activity by 46.1% at a daily dose of 50 mg kg -1 using murine malaria models infected with Plasmodium berghei. A series of protein farnesyltransferase inhibitor ester prodrugs of FTI-2148 (17) were synthesized in order to evaluate the effects of ester structure modification on antimalarial activity and for further development of a farnesyltransferase inhibitor with in vivo activity. Evaluation against P. falciparum in red blood cells showed that all the investigated esters exhibited significant antimalarial activity, with the benzyl ester 16 showing the best inhibition (ED 50 = 150 nM). Additionally, compound 16 displayed in vivo activity and was found to suppress parasitemia by 46.1% at a dose of 50 mg kg -1 day -1 against Plasmodium berghei in mice. The enhanced inhibition potency of the esters is consistent with improved cell membrane permeability compared to that of the free acid. The results of this study suggest that protein farnesyltransferase is a valid antimalarial drug target and that the antimalarial activity of these compounds derives from a balance between the hydrophobic character and the size and conformation of the ester moiety. © 2004 Elsevier Ltd. All rights reserved