Design And Synthesis Of 1, 3-Diketo Derivatives Against HIV-1 Targeting Integrase

Acquired immune deficiency syndrome (AIDS), caused by Human immunodeficiency virus (HIV), has become the most devastating public health pandemic of our time. The fatal disease has taken over 30 million people away from discovered the first patient of AIDS since 1981. Although the application of current drugs and highly active antiretroviral therapy have achieved great successes, there still exist a number of difficulties, such as the unavailable eradication of the virus, the emergence of drug resistant virus and the strong side effects. Therefore, it is of great urgency to design the novel drugs with safety and effectiveness against the new targets in the life cycle of HIV-1.HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the discovery of new anti-HIV drugs. It is involved in the integration of HIV DNA into host chromosomal DNA. There appears to have no functional equivalent in human cells and the reactions catalyzed by IN are unique. While many structurally diverse compounds have been reported to be inhibitors of HIV integrase, only a few compounds such as theβ-diketo acids, their isosteres and related compounds, represent the most convincing, biologically validated inhibitors of this viral enzyme. MK-0518 (Raltegravir) is already in clinical use and received FDA approval in October 2007. The quinolone acid GS-9137 (Elvitegravir), which has the potent prospect in application, is in the process of enrolling patients in the phase III clinical trials.We obtained the lead compounds from the results of virtual screening, the principle of bioisomerism and the natural products. We synthesized series of derivatives by further modifying the structure of the lead compounds. All of them improves the structure and activity relationship study and finally result to obtain new lead compounds with more potent biological activity.The content of the thesis contain the following major aspects: (1) Based on the structure of the integrase core domain, a preliminary search of the compounds in ACD, MDDR, NCI and Chinese Herb Database was carried out via DOCK4.0 program. Finally, 6-(1-Adamantylmethylsulfamoyl)-4-oxo-1,4-dihydro quinoline-3-carboxylic acid was selected as one of the quinolone derivatives, with lower binding energies and good drug-likeness. A series of quinolone derivatives was synthesized and their structure has been comfirmed by spectral analysis including 1H NMR, 13C NMR and Mass spectra, their inhibitory activity of HIV-1 IN strand transfer reaction was also tested by the enzyme linked immunosorbent assay (ELISA).(2) Based on the principle of bioisomerism, the pharmacophore structure of quinolone acid was conserved and the aromatic group was replaced by pyrazole at 6-position of the quinolone ring which linked two hydrophobic aromatic groups still with methylene. In order to make the hydrophobic character more clearly, two methyl groups were introduced at the 3 and 5-position on the ring of pyrazole, respectively. At the same time, halogen atoms, such as bromine and chlorine, also were introduced at 4-position on the ring of pyrazole. The substituted groups at the N-1 position on the core structure of quinolone ring could be 4-fluorobenzyl group or other groups, such as alkyl thiol. A series of quinolone derivatives was designed and synthesized. Their structure has been comfirmed by spectral analysis including 1H NMR, 13C NMR and Mass spectra and their inhibitory activity of HIV-1 IN strand transfer reaction was also tested by ELISA.(3) Based on the principle of bioisomerism and the structure of S-1360, we designed and sythesyzed a series of novel 1,3-diketo compounds, which combined the virture ofβ-diketo acids and polyhydroxylated aromatics. Compared with the structure of S-1360, the ring of furan was replaced by the ring of triazole, while the ring of triazole was replaced by substituted polyhydroxylated aromatics. Their structure has been comfirmed by spectral analysis including 1H NMR, 13C NMR and Mass spectra and their inhibitory activity of HIV-1 IN strand transfer reaction was also tested by ELISA.(4) BIAcore fastly checking technology is a useful screening method to find natural products with anti-HIV activity. Using the technology, the active compounds were separated, confirmed and their anti-HIV activities were also tested. Starting from commercially available quercetin, we synthesized the 8-(3-methylbut-2-enyl)-flavone compound and tested its anti-HIV activity. Based on the above, we designed and synthesized a series of novel compounds; their structure has been comfirmed by spectral analysis including 1H NMR, 13C NMR and Mass spectra and their anti-HIV-1 activity was also tested.