Design, Synthesis And Structure-activity Relationship Of Novel Pyrimidine Anti-HIV-1 Reverse Transcriptase Inhibitors

AIDS is mainly caused by HIV-1 and has been one of the major diseases which does harm to human health.Reverse transcriptase play an important role in the lifecycle of HIV-1,consequently,using reverse transcriptase as drug targets to design reverse-transcriptase inhibitors with high activity,selectivity,drug-resistant and hypotoxicity has become the priority in anti-AIDS study last 30 years.The HIV-1 reverse-transcriptase inhibitors are divided into NRTIs and NNRTIs.At present,5 NNRTIs have been authorized to market.They are Nevirapine,Delavirdine,Efavirenz,Etravirine,Rilpivirine,while latter two inhibitors are Diarylpyrimidines.Based on the previous studies on the SAR between DAPY and DABO compounds,3D-QSAR studies of S-DABO compounds were performed using CoMFA and CoMSIA.According to the information in the 3D contour map,it was found that the thio acetophenone at the C-2 position of the pyrimidine ring was an important role on the activity of S-DABO compounds.A series of S-DAPYs target molecular were designed based on the molecular hybridization theory.(1)According to the study of SAR,we found that Pyrimidine ring C-2 of DAPY inhibitors are located at a flexible cavity that made of amino acids which are Val106,Leu234 and Pro236.So there is enough place to transform.Combined with the 3D-QSAR of S-DABO compounds,thio acetophenone in S-DABO inhibitors was introduced into DAPY compounds.Meanwhile,the carbonyl located at the C-2 point of the side chain works as a hydrogen bond receptor and makes a better bonding effect with Lys103.The π-π stacking effect and hydrophobic effect between phenyl and the amino acids which are Val106,Leu234 and Pro236.(2)The characteristic of C-6 substituent on pyrimidine ring has a big influence on the activity of anti-HIV-1 virus for the π-πstacking effect and hydrophobic effect between C-6 substituent and the amino acids which are Tyr181,Tyr188and Trp229.In additional,we run on a docking simulation for one of the target molecular successfully,consequently,the design idea is confirmed to be reasonable respect to theory.We carry out an effective approach for synthesis of target compound accordance with the synthetic route from relative papers.Giving out the structure of pyrimidine ring by conducting a condensation reaction between thoreau and ethylacetoacetate.Pyrimidine ring and substituted bromoacetophenone have a S-alkylation reaction in K2CO3/DMF system,and the carbonyl on Pyrimidine ring is halogenated by POCl3 or POBr3.Finally,react with different substituted phenol to get target compounds in the Cs2CO3/NMP system.We got 37 newly compounds in total,The structures are characterized by NMR and IR.Some of them are analyzed by ESI-MS.