Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure-activity relationship study
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- 作者：Pillaiyar Thanigaimalai ; Sho Konno ; Takehito Yamamoto ; Yuji Koiwai ; Akihiro Taguchi ; Kentaro Takayama ; Fumika Yakushiji ; Kenichi Akaji ; Yoshiaki Kiso ; Yuko Kawasaki ; Shen-En Chen ; Aurash Naser-Tavakolian ; Arne Sch?n ; Ernesto Freire ; Yoshio Hayashi
- 关键词：SARS ; SARS-CoV 3CL protease ; Peptidomimetics ; Dipeptide ; Cysteine protease inhibitors ; Docking study
- 刊名：European Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：July, 2013
- 年：2013
- 卷：65
- 期：Complete
- 页码：436-447
- 全文大小：1311 K
文摘
This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-benzothiazole (8; Ki?=?4.1?nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CLpro. In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33?¦ÌM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1¡ä position, (ii) a ¦Ã-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position.