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In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability |
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| Authors: | Carrico Dora Ohkanda Junko Kendrick Howard Yokoyama Kohei Blaskovich Michelle A Bucher Cynthia J Buckner Frederick S Van Voorhis Wesley C Chakrabarti Debopam Croft Simon L Gelb Michael H Sebti Saïd M Hamilton Andrew D |
| Institution: | aDepartment of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520, USA bDepartment of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK cDepartments of Chemistry and Biochemistry, Campus Box 351700, University of Washington, Seattle, WA 98195, USA dDrug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Departments of Oncology and Biochemistry & Molecular Biology, University of South Florida, Tampa, FL 33612, USA eDepartment of Medicine, University of Washington, Campus Box 357185, Seattle, WA 98195, USA fDepartment of Molecular Biology and Microbiology, University of Central Florida, Orlando, FL 32826, USA |
| 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. |
| Keywords: | Plasmodium falciparum Peptidomimetic Protein farnesyltransferase Ester prodrug |
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