Design And Synthesis Of CCR5 Inhibitors Based On Piperidine-Heterocycle

AIDS is a kind of fatal immunodeficiency disease,caused by human immunodeficiency virus,and has become the most devastating public health pandemic of our time.By the end of 2014,there was more than 30 million patients of AIDS all over the world and 1.2 million people had died of AIDS or related diseases.So far,there were 28 kinds of anti-HIV-1 drugs which were approved by FDA and most of them are reverse transcriptase inhibitors and protease inhibitors.Now,highly active antiretroviral therapy is the most popular treatment clinically and it has achieved great successes.But there still exist a number of problems,such as the emergence of drug resistant virus and the strong side effects.Therefore,it is of great urgency to design the novel anti-HIV-1 drugs with safety and effectiveness.CCR5?CC-chemokine receptor 5?is a member in G protein couple receptor family and it is a coreptor which is used by HIV-1 to enter target cells.It is reported that some people with a 32-base-pair deletion?CCR5?32?are resistant to R5-tropic HIV-1.Individuals homozygous for CCR5?32 are resistant to HIV-1 infection and it has no effects on human function.It shows that CCR5 is a desire target for anti-HIV-1drug design.In 2007,the first CCR5 inhibitor,Maraviroc,was approved by FDA to use in clinic,but the resistant virus emerged soon.So it has become urgent to find new CCR5 inhibitors.Analyzing the crystal complex between CCR5 and Maraviroc and researching the binding mode between the target protein and TAK-220 by computer molecular simulation,we designed and synthesized three series compounds with piperidine bridge rings.We tested their anti-HIV-1 activities.Some characteristic compounds were explored about their anti-HIV-1 mechanism and toxicity.In addition,the preliminary structure-activity relationship was studied by Autodock 4.2.The main contents of this paper include the following aspects:?1?Using TAK-220 as the leading compound,we designed and synthesized a series of compounds with 1-benzyloctahydro-1,6-naphthyridine.We found a synthetic method to get the bridge ring,octahydro-1,6-naphthyridine,derivatives.In anti-HIV-1assay,most compounds showed good biological activities and the activities of 6compounds was less than 1?M.Among them,compound 46s has the best activity(IC₅₀=39 nM)and it provides a good leading compound for the research of CCR5inhibitors.?2?Based on the previous study,to research how the bulk and conformation of the bridge ring affect the anti-HIV-1 activity,a series of compounds with1-benzyloctahydropyrrolo[3,2-c]pyridine structure were designed and synthesized.We found a good method to synthesize the octahydropyrrolo[3,2-c]pyridine derivatives successfully.In the anti-HIV-1 assay,most of the compounds showed the anti-HIV-1activities but the activities were not so good as last series.But among them,there is a compound,61h,with IC₅₀ less than 1?M and with acceptable cytoxicity.So it can be researched further.However,in function assay,we found that there were other anti-HIV-1 targets besides CCR5.These results lay the foundation for the research of piperidine bridge ring derivatives and they can be expected to be multi-targets anti-HIV-1 drugs.?3?To research the relationship between structure and bioactivity further,we designed and synthesized a series of 1,2,3,4-tetrahydroisoquinoline derivatives.We found a synthetic method to get 1,2,3,4-tetrahydroisoquinoline derivatives with electron-withdrawing groups in 6 or 7 position.In anti-HIV-1 assay,these compounds showed antiviral activities but compare to piperidine-piperidine derivatives,their bioactivity reduced a lot.In addition,some compounds showed serious cytotoxity.So these results lay the foundation for the further optimization of piperidine derivatives.