A series of 2-(((5-akly/aryl-1 H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3 H)-ones were synthesized and their anti-HIV-1 activities were evaluated.Most of these compounds were highly active ...A series of 2-(((5-akly/aryl-1 H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3 H)-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 EC50 values in the range of0.0038-0.4759μmol/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 1-11 and 1-12 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 and4.87μmol/L for HIV-1 A17(K103 N+Y181 C).The activity against reverse transcriptase(RT)was also evaluated for those compounds.Both I-11 and 1-12 obtained sub-micromolar IC50 values showing their potential in RT inhibition.The pharmacokinetics examination in rats indicated that compound 1-11 has acceptable pharmacokinetic properties and bioavailability.Preliminary structure-activity relationships and molecular modeling studies were also discussed.展开更多
基金Financial support from the National Natural Science Foundation of China(Grant No.U1702286,21262044,81660612,21362017,21762048)Program for Changjiang Scholars and Innovative Research Team in University(IRT_17R94,China)+3 种基金The Key Scientific and Technological Program of China(2017ZX09101004-014-007)The Yunnan Applicative and Basic Research Program(P0120150150,2018FA048,China)Project of Innovative Research Team of Yunnan Province to Weilie XiaoShanghai Chem Partner Co.,Ltd.for completing the Pharmacokinetics Assays.
文摘A series of 2-(((5-akly/aryl-1 H-pyrazol-3-yl)methyl)thio)-5-alkyl-6-(cyclohexylmethyl)-pyrimidin-4(3 H)-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 EC50 values in the range of0.0038-0.4759μmol/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 1-11 and 1-12 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 and4.87μmol/L for HIV-1 A17(K103 N+Y181 C).The activity against reverse transcriptase(RT)was also evaluated for those compounds.Both I-11 and 1-12 obtained sub-micromolar IC50 values showing their potential in RT inhibition.The pharmacokinetics examination in rats indicated that compound 1-11 has acceptable pharmacokinetic properties and bioavailability.Preliminary structure-activity relationships and molecular modeling studies were also discussed.
