Synthesis And Biological Evaluation Of Piperidyl Benzimidazole Carboxamide Derivatives As Potent PARP-1 Inhibitors

For a long time,cancers have joined cardio-cerebrovascular diseases as the two major killers of human health that cause death of human beings.It was estimated that in 2018 alone,there were 18.1 million new cancer cases and 9.6 million cancer deaths worldwide.Among them,new cases and deaths accounted for 48.4%and 57.3%respectively in Asia.The development of more effective anti-cancer strategies is of great urgency.Poly（ADP-ribose）polymerases（PARPs）are a series of enzymes that play an important role in the repair of DNA damage.Among them,PARP-1 is the most abundant and deeply studied member in eukaryotic cells,which closely participates in the physiological processes of DNA repair and cell apoptosis.In recent years,PARP-1has become one of the most popular targets in the field of anti-cancer drugs.By now,a variety of PARP-1 inhibitors have entered the clinical research stage or have been approved for market.During the optimization of the phase III clinical PARP-1 inhibitor Veliparib,a precursor containing 2-（piperidin-4-yl）-1H-benzo[d]imidazole-4-carboxamide,A-620223,was screened by researchers.Its inhibitory activity against PARP-1 was below 10 nmol·L^-1 both inside and outside cells,which showed great potency.In this thesis,theresearchwasfocusedonthe2-（piperidin-4-yl）-1H-benzo[d]imidazole-4-carboxamide structural part of A-620223.Firstly,a series of 2-（piperidin-4-yl）-1H-benzo[d]imidazole-4-carboxamide derivatives were obtained through rational design of side chains according to the structure-activity relationship of PARP-1 inhibitors and synthesized;Secondly,the inhibitory activity of the target compounds against PARP-1 and PARP-2,as well as the proliferation inhibitory activity against the BRCA1/2 mutant cancer cells were assayed,and the results of bioactivity tests were analyzed from the aspect of structure-activity relationship in order to summarize the rules of changes in biological activity of2-（piperidin-4-yl）-1H-benzo[d]imidazole-4-carboxamides;In addition,the target compounds with both better and worse biological potency were selected to be involved in pharmacokinetic prediction and comparison by computational chemistry,as well as docking simulation to visually explore the binding mode of the target compounds with PARP-1.Theresultsshowedthatthe2-（piperidin-4-yl）-1H-benzo[d]imidazole-4-carboxamide PARP-1 inhibitors described in this thesis has impressive activities with the lowest IC₅₀ against PARP-1 of 2.4nmol·L^-1,as well as strong binding force with PARP-1,excellent pharmacokinetic properties as predicted,and therefore,high follow-up research value.