Design and optimization of piperidinesubstituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles  

作　　者：Yanying Sun Zhenzhen Zhou Zhongling Shi Fabao Zhao Minghui Xie Zongji Zhuo Erik De Clercq Christophe Pannecouqueb Dongwei Kang Peng Zhan Xinyong Liu 

机构地区：[1]Department of Medicinal Chemistry,Key Laboratory of Chemical Biology(Ministry of Education),School of Pharmaceutical Sciences,Shandong University,Jinan 250012,China [2]Rega Institute for Medical Research,Laboratory of Virology and Chemotherapy,K.U.Leuven,Leuven B-3000,Belgium [3]China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province,Jinan 250012,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期3110-3124,共15页药学学报（英文版）

基　　金：financial support from the National Natural Science Foundation of China(NSFC Nos.81973181,82273773);Shandong Provincial Natural Science Foundation(ZR2020YQ61,ZR2020JQ31,China);Qilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province.

摘　　要：HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIDS),but the inevitable drug resistance and side effects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors(NNRTIs).This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drugresistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(DAPY)derivatives were prepared via structural modifications of the leads K-5a2 and 25a.Among them,15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel,being 1.6-fold(WT,EC_(50) Z 1.75 nmol/L),3.0-fold(L100I,EC_(50) Z 2.84 nmol/L),2.4-fold(K103N,EC_(50) Z 1.27 nmol/L),3.3-fold(Y181C,EC50 Z 5.38 nmol/L),2.9-fold(Y188L,EC_(50) Z 7.96 nmol/L),2.5-fold(E138K,EC_(50) Z 4.28 nmol/L),4.8-fold(F227L/V106A,EC_(50) Z 3.76 nmol/L)and 5.3-fold(RES056,EC_(50) Z 15.8 nmol/L)more effective than that of the marketed drug ETR.Molecular docking results illustrated the detailed interactions formed by compound 15a and WT,F227L/V106A,and RES056 RT.Moreover,15a-HCl carried outstanding pharmacokinetic(t1/2 Z 1.32 h,F Z 40.8%)and safety profiles(LD_(50)>2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.

关 键 词：HIV-1 NNRTIS NNIBP Structural alert Anti-HIV-1 drug candidate 

分 类 号：R969.1[医药卫生—药理学]