Design,Synthesis,Biological Evaluation And Mechanism Of Benzimidazole (Benzothiazole) Derivatives

Benzimidazole and benzothiazole derivatives exhibit good biological activities,including anti-peptic ulcer,anti-cancer,anti-parasitic,antibiosis,anti-virus and anti-inflammatory analgesic with the features of high activity and low toxicity.In recent years,drug design based on modification of these two kinds of compounds has attracted more and more attention of medicinal chemists in the process of looking for more potent lead compounds with better activities.In order to find more new safe and effective anti-peptic ulcer and anti-cancer drugs,based on the structural characteristics of the DNA minor groove,two types of benzimidazoles and a class of benzothiazole compounds were designed by docking and synthesized.Eighty-three compounds were synthesized including thirty-nine series I compounds,twenty-two series II compounds and twenty-two series III compounds.Their structure were indentified with MS and 1H NMR.With the synthesized compounds in hand,we evaluated the anti-peptic ulcer and anti-cancer activities of them and found that type I benzimidazole derivatives showed good anti-peptic ulcer activity,among which eight compounds showed more than 70%inhibitory rates compared with that of pantoprazole.Meanwhile,most the compounds showed inhibitory activities to human HeLa,HL60 and U937 tomor cell line in the screening of anti-tumor experiments.However,type II benzimidazole compounds showed poor anti-ulcer activities,the acid inhibition ratio of them was lower than 60%of pantoprazole.In the anti-cancer activity evaluation of these compounds,only two of them showed good inhibitory activity to Hela,HL60 and U937 cell lines.In the other hand,benzothiazole derivatives exhibited good anti-ulcer activity,but the anti-cancer activity of them was very poor.Representative compounds with anti-cancer activity were chosed to study the mechanism of the molecules.The results of docking,UV and fluorescence spectroscopy experiments showed that the compounds can bind with DNA minor groove.And the flow cytometry,fluorescent staining test confirmed that the molecules can cause apoptosis and autophagy of the tumor cell line indeed.Finally further PBMC experiments showed that these kinds of compounds exhibited less toxicity than 5-FU and paclitaxel.All the results provided good support for the deep study of these kinds of compounds in the future.