具有改善膜通透性的拟肽类蛋白法尼基转移酶抑制剂的体外和体内抗疟活性

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

作者信息

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

机构信息

Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520, USA.

出版信息

Bioorg Med Chem. 2004 Dec 15;12(24):6517-26. doi: 10.1016/j.bmc.2004.09.020.

DOI:10.1016/j.bmc.2004.09.020

PMID:15556768

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.

摘要

为了评估酯结构修饰对抗疟活性的影响，并进一步开发具有体内活性的法尼基转移酶抑制剂，合成了一系列FTI-2148（17）的蛋白质法尼基转移酶抑制剂酯前药。对红细胞内恶性疟原虫的评估表明，所有研究的酯都表现出显著的抗疟活性，其中苄酯16表现出最佳抑制效果（ED50 = 150 nM）。此外，化合物16显示出体内活性，发现在50 mg kg(-1) 天(-1) 的剂量下对小鼠伯氏疟原虫的抑制率为46.1%。与游离酸相比，酯的抑制效力增强与细胞膜通透性提高一致。本研究结果表明，蛋白质法尼基转移酶是一个有效的抗疟药物靶点，这些化合物的抗疟活性源于酯部分的疏水特性与大小和构象之间的平衡。