Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

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.