Structure-directed expansion of biphenyl-pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with significantly improved potency and safety  

作　　者：Li-Min Zhao Christophe Pannecouque Erik De Clercq Shuai Wang Fen-Er Chen 

机构地区：[1]Engineering Center of Catalysis and Synthesis for Chiral Molecules,Department of Chemistry,Fudan University,Shanghai 200433,China [2]Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,Shanghai 200433,China [3]Key Laboratory of Natural Resources of Changbai Mountain&Functional Molecules,Ministry of Education,Yanbian University College of Pharmacy,Yanbian University,Yanji 133002,China [4]Rega Institute for Medical Research,KU Leuven,Herestraat 49,Leuven B-3000,Belgium

出　　处：《Chinese Chemical Letters》2023年第12期126-131,共6页中国化学快报（英文版）

基　　金：funded by the National Natural Science Foundation of China(No.22077018).

摘　　要：Following our previous work on human immunodeficiency virus-1(HIV-1)non-nucleoside reverse transcriptase inhibitors(NNRTIs),a series of novel biphenyl-pyridone derivatives were synthesized and evaluated for their anti-HiV-1 activity to expand their structure-activity relationship.Some of them exhibited low nanomolar activity toward wild-type HiV-1 and clinically relevant single/double mutant strains.The most active compound B1 was 231-fold more potent(EC_(50)=17nmol/L)than the lead compound 2(EC_(50)=3.93μmol/L)against wild-type(WT)HIV-1.This compound was approximately 3.5-fold less cytotoxic(CC_(50)=100.58μmol/L)than compound 2(CC_(50)=28.24μmol/L),presenting a higher selectivity index(SI)value of 5923.Compared with 2,the antiviral potency of B1 was significantly increased against five single mutant strains(L1001,K103N,E138K,Y181C and Y188L)and two double mutant strains(F227L+V106A and K103N+Y181C).Especially,K103N,Y181C and K103N+Y181C were more sensitive to B1 than both 2 and doravirine.Besides,the enzymatic inhibitory activity of B1 against wild-type HIV-1 reverse transcriptase was approximately 32-fold higher(IC_(50)=100nmol/L)than 2(IC_(50)=3.21μmol/L).Molecular docking studies and dynamic simulations were conducted to explain their potent activity.Taken together,this research represents an important step toward the discovery of novel biphenylpyridone drug candidates for HIV therapy.

关 键 词：HIV-1 NNRTI Doravirine Biphenyl-pyridone SAFETY 

分 类 号：TQ460.1[化学工程—制药化工]