Synthesis of di- and tripeptide analogues containing α-ketoamide as a new core structure for inhibition of HIV-1 protease

被引:75
作者
Sheha, MM
Mahfouz, NM [1 ]
Hassan, HY
Youssef, AF
Mimoto, T
Kiso, Y
机构
[1] Assiut Univ, Fac Pharm, Dept Pharmaceut Med Chem, Assiut 71526, Egypt
[2] Japan Energy Co, Pharmaceut & Biotechnol Lab, Kyoto, Japan
[3] Kyoto Pharmaceut Univ, Dept Med Chem, Yamashima Ku, Kyoto 6078414, Japan
关键词
dipeptides; tripeptides; alpha-ketoamides; HIV-1; protease; inhibitory activity; QSAR;
D O I
10.1016/S0223-5234(00)00187-2
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Di- and tripeptide analogues containing alpha -ketoamide as a new core structure and incorporating allophenylnorstatine (Apns) as a transition state mimic, were designed and synthesized in the hope of obtaining a novel structural type of HIV-1 protease inhibitors. The immediate precursor, Apns-Thz-NHBu(t) was prepared by coupling of Boc-Apns with N-tert-butyl Thz-4-carboxamide hydrochloride. Removal of Boc group followed by coupling with the respective alpha -ketoacid residue (P2) gave the desired dipeptides (8-12) in almost quantitative yields. The alpha -keto tripeptides (18-21) were obtained by oxidation of the hydroxyl group of Apns (PI) in the appropriate tripeptide, iQOA-Val-Apns-(un)substituted Thz(Oxa)-NHBu(t) with DMSO/DCC. Preliminary evaluation of the activity of the synthesized derivatives was determined as percentage of enzyme inhibition at 5 muM and 50 nM levels of the di- and tripeptides respectively. The alpha -ketoamides displayed a significant enhanced potency relative to their parent isosteres as inhibitors of HIV-1 protease and are shown to be a promising new core structure for the development of enzyme inhibitors. A quantitative approach was attempted, using an LFE model, correlating the effect of structural modification and HIV-1 protease inhibition activity of the prepared dipeptides. The result indicates the contribution of the torsion angle by 84% to the activity of the inhibitors. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
引用
收藏
页码:887 / 894
页数:8
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