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.
In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones were designed,synthesized and evaluated for their antiviral activities in MT-4 cells.Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC_(50) values ranging from 7.55μmol/L to 0.018μmol/L.Among them,compound 5 c was identified as the most promising inhibitor against HIV-1 replication with an IC_(50)=0.018μmol/L,CC_(50)=194μmol/L,and SI=12791,which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV.In addition,5 c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02.The preliminary structure-activity relationship(SAR)and molecular modeling studies were also discussed,which provides some useful indications for guiding the further rational design of new S-DACO analogues.
Daxiong LiChunsheng ZhangWei DingSiming HuangLe YuNan LuWenkai PanYiming LiErik De ClercqChristophe PannecouqueHongbing ZhangYueping WangYanping HeFener Chen
