Molecular Design,Synthesis And Anti-HIV Activity Research Of S-DACOs And NH-DACOs NNRTIs

The HIV virus infection causes acquired immunodeficiency syndrome(AIDS)that is a fatal human health-threatening disease.AIDS is a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive.At present,AIDS has been listed as one of the major diseases that seriously threaten human's life and health.Studies have shown that preventing any step of the HIV growth cycle can inhibit HIV virus replication.Now,the reverse transcription in the HIV growth cycle have been identified as potential targets for drug design.Our continuing interest in the search for new NNRTIs led us recently to describe the design and synthesis of a new series of 6-Cyclohexyl methyl substituted S-DACO analogues as highly potent HIV-1 inhibitors.In this paper,we studied the putative binding mode of S-DACO derivatives(LXF series compounds)to the active site of RT by Autodock program to achieve further modifications on this series of NNRTIs.Based on the the docking analysis of LXF series compounds/RT complexes,a new series of 4-(((4-(cyclohexylmethyl)-5-alkyl-6-oxo-1,6-dihydropyrimidin-2-yl)oxy)methyl)phenyl-substituded benzoate and 6-(cyclohexylmethyl)-5-alkyl-2-((4-substituted benzyl)amino)-pyrimidin-4(3H)-one derivatives were designed and synthesized with the hope to find more potent HIV-1 RT inhibitors with improved drug pharmacokinetic properties.The key immediate 2-thiourea pyrimidine ketone were synthesized by improved Clay and Blaise routes.The side chain compounds 4-(bromomethyl)phenyl-substituted benzoate and 4-(2'-bromoacetyl)substituted ester were obtained by using as raw materials synthesized by the method of p-cresol or p-hydroxy phenol reacts with aromatic chloride to get the p-tolyl-substituted benzoate and 4-formylphenyl-substituted benzoate.Then,the p-tolyl-substituted benzoate reaction with NBS and AIBN to obtain side chain compounds.In addition,reduction of 4-formylphenyl-substituted benzoate with NaBH4 to produced the 4-(hydroxymethyl)phenyl-substituted benzoate,and then nucleophilic substitution of 4-(hydroxymethyl)phenyl-substituted benzoate with phosphorus tribromide in methylene dichloride yielded the corresponding 4-(bromomethyl)phenyl-substituted benzoate.Followed 2-thiourea pyrimidine ketone reacts with 4-(bromomethyl)phenyl-substituted benzoate and 4-(2'-bromoacetyl)-substituted ester to get the 4-(((4-(cyclohexylmethyl)-5-alkyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)thio)methyl)phenyl-substituded benzoate.At last,the 27 target compounds were synthesized by above method.Furthermore,The N-3 position of NH in 2-thiomethyl pyrimidine is protected by(Boc)2O,then oxidized with m-CPBA to get the 2-methanesulfonyl pyrimidone.Finally,the 2-methanesulfonyl pyrimidone react with multi-substituted amines in Et3N and 120 C to obtained the target 6-(cyclohexylmethyl)-5-alkyl-2-((4-substituted benzyl)amino)pyrimidin-4(3H)-one analogues.In our research,Through exploring the synthetic route,We simplify the synthesis operation and increase the yield.At last,12 unreported target compounds are synthesized by this method.In summary,this method shows a clear advantages over the methods reported previously.Thus,We have synthetised 39 new target compounds with facilitate easy experimental operatiom,The structures of the target compounds were characterized by 1H NMR,13C NMR,IR and HRMS.In this paper,the test work of the anti HIV virus activity of the compounds was cooperated with the Kunming Institute of Zoology·CAS,and the screening of the biological activity of the compounds is stillon going.