首页|Design and optimization of piperidine-substituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles
Design and optimization of piperidine-substituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles
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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 ef-fects 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 drug-resistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(DAPY)de-rivatives 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,EC50=1.75 nmol/L),3.0-fold(L100I,EC50=2.84 nmol/L),2.4-fold(K103N,EC50=1.27 nmol/L),3.3-fold(Y181C,EC50=5.38 nmol/L),2.9-fold(Y188L,EC50=7.96 nmol/L),2.5-fold(E138K,EC50=4.28 nmol/L),4.8-fold(F227L/V106A,EC50=3.76 nmol/L)and 5.3-fold(RES056,EC50=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=1.32 h,F=40.8％)and safety profiles(LD50＞2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.
HIV-1NNRTIsNNIBPStructural alertAnti-HIV-1 drug candidate
Yanying Sun、Zhenzhen Zhou、Zhongling Shi、Fabao Zhao、Minghui Xie、Zongji Zhuo、Erik De Clercq、Christophe Pannecouque、Dongwei Kang、Peng Zhan、Xinyong Liu
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Department of Medicinal Chemistry,Key Laboratory of Chemical Biology(Ministry of Education),School of Pharmaceutical Sciences,Shandong University,Jinan 250012,China
Rega Institute for Medical Research,Laboratory of Virology and Chemotherapy,K.U.Leuven,Leuven B-3000,Belgium
China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province,Jinan 250012,China
National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaShandong Provincial Natural Science Foundation,ChinaShandong Provincial Natural Science Foundation,ChinaQilu Young Scholars Program of Shandong University and Taishan Scholar Program at Shandong Province
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