Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors  

作　　者：Daxiong Li Chunsheng Zhang Wei Ding Siming Huang Le Yu Nan Lu Wenkai Pan Yiming Li Erik De Clercq Christophe Pannecouque Hongbing Zhang Yueping Wang Yanping He Fener Chen 

机构地区：[1]Key Laboratory of Medicinal Chemistry for Natural Resource,Ministry of Education,Yunnan Research&Development Center for Natural Products,School of Chemical Science and Technology,Yunnan University,Kunming 650091,China [2]Rega Institute for Medical Research,KU Leuven,Herestraat 49,B-3000,Leuven,Belgium [3]Department of Applied Chemistry,Faculty of Science,Kunming University of Science and Technology,Kunming 650500,China [4]Engineering Center of Catalysis and Synthesis for Chiral Molecules,Department of Chemistry,Fudan University,Shanghai 200433,China [5]Office of Academic Affairs,Yunnan University of Finance and Economics,Kunming 650221,China

出　　处：《Chinese Chemical Letters》2021年第3期1020-1024,共5页中国化学快报（英文版）

基　　金：financial support from the National Natural Science Foundation of China(Nos.21967020,U1702286,21362017,21262044);Program for Changjiang Scholars and Innovative Research Team in University(No.IRT17R94,China);Fund of Academician Working Station of Yunnan Province(No.2018IC057)。

摘　　要：In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones were designed,synthesized and evaluated for their antiviral activities in MT-4 cells.Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC_(50) values ranging from 7.55μmol/L to 0.018μmol/L.Among them,compound 5 c was identified as the most promising inhibitor against HIV-1 replication with an IC_(50)=0.018μmol/L,CC_(50)=194μmol/L,and SI=12791,which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV.In addition,5 c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02.The preliminary structure-activity relationship(SAR)and molecular modeling studies were also discussed,which provides some useful indications for guiding the further rational design of new S-DACO analogues.

关 键 词：NNRTIS S-DABOs S-DACOs Anti HIV-1 activity SAR 

分 类 号：TQ460.1[化学工程—制药化工]