Synthesis and biological evaluation of a series of 2-(((5-akly/aryl-1-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3)-ones as potential HIV-1 inhibitors.
10.1016/j.apsb.2019.08.009
- Author:
Yumeng WU
1
;
Chengrun TANG
2
;
Ruomei RUI
1
;
Liumeng YANG
2
;
Wei DING
1
;
Jiangyuan WANG
1
;
Yiming LI
1
;
Christopher C LAI
3
;
Yueping WANG
1
;
Ronghua LUO
2
;
Weilie XIAO
1
;
Hongbing ZHANG
1
;
Yongtang ZHENG
2
;
Yanping HE
1
Author Information
1. 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.
2. 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.
3. Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
- Publication Type:Journal Article
- Keywords:
Antiviral activity;
HIV-1;
Molecular modeling;
NNRTIs;
S-DABOs;
SAR
- From:
Acta Pharmaceutica Sinica B
2020;10(3):512-528
- CountryChina
- Language:English
-
Abstract:
A series of 2-(((5-akly/aryl-1-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3)-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 EC values in the range of 0.0038-0.4759 μmol/L. Among those compounds, had an EC value of 3.8 nmol/L and SI (selectivity index) of up to 25,468 indicating excellent activity against WT HIV-1. anti-HIV-1 activity and resistance profile studies suggested that compounds and displayed potential anti-HIV-1 activity against laboratory adapted strains and primary isolated strains including different subtypes and tropism strains (ECs 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 EC values of 2.77 and 4.87 μmol/L for HIV-1A (K103N + Y181C). The activity against reverse transcriptase (RT) was also evaluated for those compounds. Both and obtained sub-micromolar IC values showing their potential in RT inhibition. The pharmacokinetics examination in rats indicated that compound has acceptable pharmacokinetic properties and bioavailability. Preliminary structure-activity relationships and molecular modeling studies were also discussed.
