European Journal of Medicinal Chemistry p. 887 - 894 (2000)
Update date:2022-08-11
Topics:
Sheha, Mahmoud M.
Mahfouz, Nadia M.
Hassan, Hoda Y.
Youssef, Adel F.
Mimoto, Tsutomu
Kiso, Yoshiaki
Di- and tripeptide analogues containing α-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 α-ketoacid residue (P2) gave the desired dipeptides (8-12) in almost quantitative yields. The α-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)-NHBu1 with DMSO/DCC. Preliminary evaluation of the activity of the synthesized derivatives was determined as percentage of enzyme inhibition at 5 μM and 50 nM levels of the di- and tripeptides respectively. The α-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.
View MoreShanghai He Yang International Trading Co., Ltd.
Contact:+86-21-52043598
Address:Room 816, Blag.5, No.58 Huachi Road
Landz International Company Ltd.
Contact:0086-21-58891610
Address:985 Dongfang Road, Pudong, Shanghai 200122 China
Beijing Mashi Fine Chemical Co.,Ltd.
Contact:+86-10-61271592
Address:Room 506, Section B, Kaichi Mansion, Industrial Development
HANGZHOU ZHONGCHANG SCIENTIFIC CO.,LTD
Contact:+86-571-88932183
Address:Hangzhou
Xinchang Yueding Chemical Co., Ltd.
Contact:86-571-56926323
Address:NO.90 BEIMENCHENGWAI CHENGGUAN TOWN XINCHANG
Doi:10.1021/ic034826o
(2004)Doi:10.1080/10426509608046388
(1996)Doi:10.1021/acs.joc.6b00374
(2016)Doi:10.1039/d0cy00409j
(2020)Doi:10.1002/jlcr.2590090310
(1973)Doi:10.1016/S0040-4039(97)10273-8
(1997)