首页|Synthesis and biological evaluation of a series of 2-(((5-akly/aryl-1H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones as potential HIV-1 inhibitors

Synthesis and biological evaluation of a series of 2-(((5-akly/aryl-1H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones as potential HIV-1 inhibitors

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A series of 2-(((5-akly/aryl-lH-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones were synthesized and their anti-HIV-1 activities were evaluated.Most of these compounds were highly active against wild-type (WT) HIV-1 strain (IIIB) with ECso values in the range of 0.0038-0.4759 μmol/L.Among those compounds,Ⅰ-11 had an EC50 value of 3.8 nmol/L and SI (selectivity index) of up to 25,468 indicating excellent activity against WT HIV-1.In vitro anti-HIV-1 activity and resistance profile studies suggested that compounds Ⅰ-11 and Ⅰ-12 displayed potential anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (EC50s range from 4.3 to 63.6 nmol/L and 18.9-219.3 nmol/L,respectively).On the other hand,it was observed that those two compounds were less effective with EC50 values of 2.77 and 4.87 μmol/L for HIV-1A17 (K103N + Y181C).The activity against reverse transcriptase (RT) was also evaluated for those compounds.Both Ⅰ-11 and Ⅰ-12 obtained sub-micromolar IC5o values showing their potential in RT inhibition.The pharmacokinetics examination in rats indicated that compound Ⅰ-11 has acceptable pharmacokinetic properties and bioavailability.Preliminary structure-activity relationships and molecular modeling studies were also discussed.

HIV-1NNRTIsS-DABOsAntiviral activitySARMolecular modeling

Yumeng Wu、Chengrun Tang、Ruomei Rui、Liumeng Yang、Wei Ding、Jiangyuan Wang、Yiming Li、Christopher C.Lai、Yueping Wang、Ronghua Luo、Weilie Xiao、Hongbing Zhang、Yongtang Zheng、Yanping He

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Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China

Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, the National Kunming High Level Biosafety Research Center for Nonhuman Primate, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China

School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical Un

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA

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Financial support from the National Natural Science Foundation of ChinaProgram for Changjiang Scholars and Innovative Research Team in UniversityProgram for Changjiang Scholars and Innovative Research Team in UniversityKey Scientific and Technologi

21762048IRT_17R94China

2020

药学学报(英文版)

药学学报(英文版)

CSTPCDCSCDSCI
ISSN：
年,卷(期)：2020.10(3)
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