首页|Structure-based design and optimization lead to the identification of novel dihydrothiopyrano[3,2-d]pyrimidine derivatives as potent HIV-1 inhibitors against drug-resistant variants

Structure-based design and optimization lead to the identification of novel dihydrothiopyrano[3,2-d]pyrimidine derivatives as potent HIV-1 inhibitors against drug-resistant variants

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With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the dis-covery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse tran-scriptase inhibitors.To fully explore the chemical space of the NNRTI-binding pocket,novel series of dihydrothiopyrano[3,2-d]pyrimidines were developed by employing the structure-based design strategy.Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels.Among them,compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor,with EC50 values ranging from 3.43 to 21.4 nmol/L.Espe-cially,for the challenging double-mutants F227L+V106A and K103N+Y181C,23h exhibited 2.3-to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine.Besides,the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine.The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase.Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign.Furthermore,no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h.Most importantly,23h was characterized by good pharmacokinetic properties and excellent safety in vivo.Collectively,23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.

HIV-1Reverse transcriptaseDihydrothiopyrano[3,2-d]pyrimidineAntiviral agent

Zhao Wang、Heng Zhang、Zhen Gao、Zihao Sang、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,Cheeloo College of Medicine,Shandong University,Jinan 250012,China

China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province,Jinan 250012,China

Suzhou Research Institute,Shandong University,Suzhou 215123,China

Rega Institute for Medical Research,Laboratory of Virology and Chemotherapy,K.U.Leuven,Leuven B-3000,Belgium

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国家自然科学基金国家自然科学基金Science Foundation for Outstanding Young Scholars of Shandong ProvinceScience Foundation for Excellent Young Scholars of Shandong ProvinceForeign Cultural and Educational Experts Project中国博士后科学基金Shandong Province Natural Science Foundation for Youths江苏省自然科学基金Qilu Young Scholars Program of Shandong UniversityTaishan Scholar Program at Shandong Province

8197318181903453ZR2020JQ31ZR2020YQ61GXL202000150012022M721948ZR2023QH217BK20230252

2024

10.1016/j.apsb.2023.11.023

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(3)
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