The Design, Synthesis And Structure-activity Relationship Study Of Pyridino Heterocyclic Compounds Targeting To HIV-1 Integrase

The AIDS is an abbreviation of acquired immunodeficiency syndrome caused by HIV effection, which is a contagion, has serious threat to human health. Since the AIDS was first discovered in America in Jane 1981 to the end of 2015, this disease has caused 3 million peoples’ death. The highly active antiretroviral combination therapy(HAART) is now the best therapy method to AIDS, but the drug resistance strain caused by fast variation of HIV and the side effect of drug indicated that finding a new drug to cure the AIDS is to be solved.There are three key enzymes during the pol gene coding procedure: revertase, protease and integrase. The integrase is a 32 kd protein, which can catalyst the virus DNA integrates to the parasitifer RNA. But there are no function-similar or homology enzymes in human body, thus the HIV integrase is an ideal target for anti-HIV drug designation. Since 2007, there have been three integrase inhibitors to be available for sale: Raltegravir, Elvitegravir and Dolutegravir. But the drug tolerance virus strain has been appeared step by step because of the high mutability of HIV, which indicated that to find a new drug is extremely urgent.By study the pharmacophore and the bioisosterism method, we designed three new parent nucleuses base on the reported compound. According to joint different groups to the designed parent nucleuses, three serials compounds were designed and synthesized successful. The activities were determinate on molecular level and cell level. Finally, we got the reasons of the different activity of these compounds.by using the molecular docking method, the binding mode of compounds with HIV integrase and their Structure-Activity Relationships of Anti-IN Based on these results, it is expected to design and synthesize better integrase inhibitors.The main contents of this paper include the following aspects:(1) Combine with the structure properties of three integrase inhibitors in the market and three N-hydroxy integrase inhibitors, the imidazo-piperidine derivativess(J1-10 a ~ J1-10s) and thiazolo-piperidine derivativess(J2-12 a ~ J2-12s) were designed. The structure activity relationship of designed compounds were analysized by coulping different hydrophobic aromatic group to C-12 position of imidazo-piperidine and thiazolo-piperidine core, respectively. To avoid the unreasonable designation of these compounds, the binding mode, docking energy and inhibit activity of two representative compounds were performed by molecular docking program.(2) Based on previous reports of N-hydroxy-dihydronaphthylamine derivatives, and raltegravir, we designed a new series of N-hydroxy-dihydronaphthylamines and introduced various hydrophobic group in the core of the C-2 position in order to investigate the relationship between activity and structure, then, a series new N-hydroxy-dihydronaphthylamine derivatives(J3-8a~J3-8l) were synthesized.. The anti-IN 3’-P, ST and anti-HIV activity of these compounds were also measured. Finally with the help of molecular docking method, the binding mode and docking energy of representative compounds were got. The structure activity relationship of these compounds was also analyzed by the results of docking. These results lay the foundation for the further optimization of these compounds.(3) Diketone acids HIV-1 integrase inhibitors are a class of compounds with good prospect. In order to explore the new integrase inhibitors, the launched anti-HIV drug raltegravir was selected as template compounds. According to the concept of bioisosterism, pyridine-pyrrole core was designed, and a series of pyridine-2-formyl-pyrrole derivatives(J4-6a~J4-6t) were synthesized by coupling various hydrophobic aryl to C-10 position of the core. The anti-IN 3’-P and anti-HIV activity of these compounds were also measured. Finallyhe structure activity relationship of these compounds was also analyzed by the results of docking. These results lay the foundation for the further optimization of these compounds.(4) On the basis of the structure of the pyridine-2-formoyl-pyrrole derivatives, 6-substitute pyridine-pyrrolo core was designed by analysis of differences binding mode between the pyridine-pyrrolo(J4-6i) and Raltegravir via molecular docking method. Compounds(J5-7a ~ J5-7i) were synthesized by coupling a series of hydrophobic groups to C-6 position of 6-substitute pyridine-pyrrolo core. The anti-IN 3’-P and anti-HIV activity of these compounds were also measured. Finally, the structure activity relationship of these compounds was also analyzed by the results of docking. These results lay the foundation for the further optimization of these compounds.