Design And Synthesis Of Quinolone Acids As Potential HIV-1 Integrase Inhibitors

Acquired immune deficiency syndrome(AIDS) is one of the most devastating contagions. The viral enzyme integrase(IN) is crucial for its replication. Since there is no counterpart in human cells, inhibitors with high selectivity show lower toxicity. Consequently, HIV-1 IN has been a hot target for development of new anti HIV-1 drugs.The compounds with β-diketone acid moiety show high anti HIV-1 activity. Quinolone acid, a kind of bioisostere of β-diketones also shows bioactivity like β-diketone. The binding mode between GS-9137, an U.S. FDA approved inhibitor, and target protein as well as the structure-activity relationship of GS-9137 were analyzed. It was found that the benzyl moiety on GS-9137 can insert the hydrophobic cavity in IN. Thus the benzyl moiety should be of significance for the bioactivity. This dissertation is about to improve bioactivity and pharmacokinetic property of GS-9137 through adjusting the orientation of the benzyl moiety by replacing the benzyl group and methoxy group with a N-benzyl morpholine. Compounds with [1,4]oxazino[3,2-g] quinolone acid moiety and [1,4]oxazino[2,3-g]quinoline moiety was designed.According to retrosynthetic analysis and optimization, a reasonable synthesis route was obtained. Eighteen unreported [1,4]oxazino[3,2-g]quinolone acid compounds were synthesized through 2-amino-5-nitrophenol in nine-steps reaction. Twelve unreported [1,4]oxazino[2,3-g]quinoline compounds were synthesized through 2-amino-4-nitrophenol in nine-steps reaction.The structure of the intermediates was confirmed by 1H NMR, and the target compounds were confirmed by 1H NMR,13 C NMR and HRMS. The bioactivity of the [1,4]oxazino[3,2-g]quinolone acid compounds was tested and the half maximal inhibitory concentration(IC50) of compound 10 m is 190 nM. It provides valid foundation for further study.