In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability
| Autor: | Frederick S. Buckner, Debopam Chakrabarti, Michael H. Gelb, Wesley C. Van Voorhis, Dora Carrico, Saïd M. Sebti, Michelle A. Blaskovich, Simon L. Croft, Howard Kendrick, Andrew D. Hamilton, Cynthia Bucher, Kohei Yokoyama, Junko Ohkanda |
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| Rok vydání: | 2004 |
| Předmět: |
Cell Membrane Permeability
Erythrocytes Membrane permeability Plasmodium berghei Farnesyltransferase Plasmodium falciparum Clinical Biochemistry Pharmaceutical Science Biochemistry Antimalarials Mice Structure-Activity Relationship In vivo Drug Discovery Animals Farnesyltranstransferase Structure–activity relationship Molecular Biology Farnesyl-diphosphate farnesyltransferase Alkyl and Aryl Transferases biology Chemistry Molecular Mimicry Organic Chemistry Farnesyltransferase inhibitor Esters Biological activity Malaria Enzyme inhibitor NIH 3T3 Cells biology.protein Molecular Medicine Peptides Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Bioorganic & Medicinal Chemistry. 12:6517-6526 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2004.09.020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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