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

• 来源期刊: 药学学报（英文版）
• 关键词: HIV-1 NNRTIs S-DABOs Antiviral activity SAR Molecular modeling
• 年，卷（期）: 2020,（3）
• 页码范围: 512-528
• 页数: 17页
• 语种: 英文

摘要

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.