Molecular Design,synthesis And Biological Activity Of HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Reverse transcriptase plays an important role in the life cycle of HIV-1.Reverse transcriptase inhibitors,which target at HIV-1 RT,are important components of highly active anti-retroviral therapy.Diaryl pyrimidines?DAPYs?as the second generation of non-nucleoside reverse transcriptase inhibitors have been paid much attention for its high efficiency and low toxicity.The modification of DAPYs were centered on the central pyrimidine ring,the left wing aromatic ring and the linker between central pyrimidine ring and left wing.In this work,a new family of DAPYs featuring a diatomic linker was designed using Etravirine as lead compound to improve the conformational flexibility and positional adaptability of molecules,and further enhance strong?-?stacking with the amino acid residues Tyr181,Tyr188 and Trp229.And the left pheyl was also modified as pyridinyl.The docking between designed compounds and HIV-1 RT verified the rationality of design.The target compounds were prepared according to synthetic procedures as follows:2-?methylthio?pyrimidin-4?1H?-one?2b?was synthesized from 2-thiouracil using iodomethane as methylation reagent.2b reacted with the cyanide aniline in the meltingconditionstoafford4-??4-oxo-1,4-dihyd-ropyrimidin-2-yl?amino?-benzonitrile?2c?,which was chlorinated in the presence of phosphorus oxychloride to obtain 4-??4-chloropyrimidin-2-yl?amino?benzonitrile?2d?.Finally,30 different title compounds LH1a-x and LH2a-d were prepared by nucleophilic substitution between benzyl alcohol/heteroaryl methanol and 2d in the presence of base.All of new compounds were characterized by ¹H NMR,¹³C NMR and mass spectra.All of target compounds were evaluated for their anti-HIV activities and cytotoxicity.Most of the compounds displayed excellent activities against wild-type HIV-l,low cytotoxicities and high selectivity index.Among them,four compounds displayed extremely potent activities against wild-type HIV-l with EC₅₀ values of less than 10 nM,and the most active compound LH1g(EC₅₀=5.8 nM)is superior to the second generation NNRTI efavirenz.Moreover,some compounds exhibited moderate activites against E138K mutants,for example,LH2b showd an EC₅₀ of 0.24?M.The structure-activity relationships were also summarized,which provided a reference for further design and development of more efficient HIV-1 RT inhibitors.