Synthesis And Molecular Docking Towards HIV-1 Integrase Of 2-Aryl Dihydrobenzofuran Compounds

Objective: Synthesis of 2-aryl dihydrobenzo[b]furan compounds and molecular docking with the HIV-1 integrase enzyme(PDB: 1QS4) for analyzing binding manner with the enzyme and inhibitory effect. Methods: 1. 2-Aryl dihydrobenzo[b]furan moiety of compound 7 was built from vanillin and malonic acid through Knoevenagel condensation, esterification, and oxidation coupling reaction. 2. compound 9: was synth- sized from compound 2 through esterification and oxidative coupling reaction. 3. Compound 11 was synthesized from compound 2 through acylation and oxidative coupling reaction. 4. 1.3-Dione acid moiety was introduced through Friedel-Crafts acetylation reaction and condensation reaction under sodium methoxid and dimethyl oxalate for synthesis of compound 13, then hydrolyzed to compound 14. 5. Molecular docking towards HIV-1 integrated(1QS4 PDB:) aided by computer and software of Aut- dock Vina, for analyzing compounds inhibitory effects. Results: The yield of compound 9 was of 21.4%, and chemical structure elucidated by NMR and other spectroscopic techniques of(E)-5-[2-(4-hydroxy-3-methoxy)phenyl-7-methoxy-3-methoxycarbonylacetyl-2,3-dihydro benzo[b]furan-5-yl]-3-oxo-pent-4-enate. The yield of compound 11 was of 1.1%, and chemical structure elucidated by NMR and other spectroscopic techniques of(E)-N-(methoxycarbonyl)methyl-3-[2-(4-hydroxy-3-methoxy)phenyl-7-methoxy-3-[[[[met hoxycarbonyl]methyl]amino]carbonyl]-2,3-dihydrobenzo[b]furan-5-yl]acrylamide. The yield of compound 13 was of 44.8%, and chemical structure elucidated by NMR and other spectroscopic techniques of(E)-3-[2-(4-hydroxy-3-methoxy-5-methoxycarbonylacetyl) phenyl-3-methoxycarbonyl-7-methoxy-2,3-dihydrobenzo[b]furan-5-yl]acrylate. The yield of compound 14 was of 25.3%, and chemical structure elucidated by NMR and other spectroscopic techniques of(E)-3-[2-hydroxy-3-methoxy-5-[5-[2-[methoxycarbonyl]vinyl]-7-methoxy-3-methoxcarbonyl-2,3-dihydrobenzo[b]furan-2-yl]-3-oxo-propanoic acid. Molecular docking showed that amino acid residues in the compound 9、11、13、14 and HIV-1 integrase(PDB:1QS4) exists between hydrogen bonds and π-π conjugated stack and hydrophobic interactions. Synthesis of intermediate compound 2:(E)-3-(4- hydroxy-3-methoxyphenyl) acrylic acid, yield 90.7%、Compound 3:(E)-3-(4-hydroxy-3-methoxyphenyl) methyl propene, yield 78.1%、Compound 5:(E)-3-(4-hydroxy-2-methoxyphenyl) acrylic acid, yield 85.0% 、 Compound 6:(E)-3-(4-hydroxy-2-meth oxyphenyl) methyl propene, yield 57.0%、Compound 7:(E)-3-[2-(4-hydroxy-3- methoxy) phenyl-3-methoxycarbonyl-7-methoxy-2,3-dihydrobenzo[b]furan-5-yl]acrylate, yield 37.2%、Compound 8:(E)-3-(4-hydroxy-3-methoxyl)-2-methoxy-2-oxoethylphenyl acrylate, yield 45.6%、Compound 10:(E)-3-(4-hydroxy-2-methoxyphenyl) acryloyl glycine, yield 33.8%、Compound 12:(E)-3-[2-(4-hydroxy-3-methoxy-5-acetyl) phenyl-3-methoxy carbonyl-7-methoxy-2,3-dihydrobenzo[b]furan-5-yl]acrylate, yield 33.8%、Compound 15:(E)-3-[2-(4-acetyl-3-methoxy)phenyl-3-methoxycarbonyl-7- methoxy-2,3-dihydrobenzo [b]furan-5-yl]acrylate, yield 45.7%. Conclusion: This study adopts the shorter synthetic route, mild reaction conditions, simple operation and easy control method for constructing the oxidative coupling of 2-aryl dihydrobenzofuran skeleton structure of the compound 7, also obtained by oxidative coupling of the target compound 9 and 11. On the basis of 2-aryl dihydrobenzofuran skeletal structure of compound 7 by the Friedel-Crafts reaction, compound 13 synthesized substituted, Compound 13 by hydrolysis target compound 14. Each product was purified by column chromatography and spectroscopy confirmed the structure. the synthesis of the target compound 9,11,13,14 to HIV-1 integrase(1QS4) as a target, the molecular docking analysis revealed the presence of hydrogen bonds between the target compound and integrase amino acid residues, π-π-conjugate composite function and hydrophobic force, the compound 9,11,13,14 has the effect of inhibiting HIV-1 integrase enzymes. The combination of the binding energy and hydrogen bonding is the most principle analysis of compounds 14 and HIV-1 integration of the enzyme is more stable, inhibit the HIV-1 integrated enzyme activity stronger.