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

Publication date: Available online 5 September 2019Source: Acta Pharmaceutica Sinica BAuthor(s): 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 HeAbstractA series of 2-(((5-akly/aryl-1H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3H)-ones were synthesized and their anti-HIV-1 activities was evaluated. Most of these compounds were highly active against wild-type (WT) HIV-1 strain (IIIB) with EC50 values in the range of 0.0038 to 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 IC50 values showing their potential in RT inhibition. The pharmacokinetics examination in rats indicated that compound I-11 ha...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research