2. Academic Validation
  3. In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability

In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability

  • Bioorg Med Chem. 2004 Dec 15;12(24):6517-26. doi: 10.1016/j.bmc.2004.09.020.
Dora Carrico 1,  Junko Ohkanda,  Howard Kendrick,  Kohei Yokoyama,  Michelle A Blaskovich,  Cynthia J Bucher,  Frederick S Buckner,  Wesley C Van Voorhis,  Debopam Chakrabarti,  Simon L Croft,  Michael H Gelb,  Saïd M Sebti,  Andrew D Hamilton
Affiliations

Affiliation

  • 1 Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520, USA.
PMID: 15556768 DOI: 10.1016/j.bmc.2004.09.020
Abstract

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 (ED50=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.

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