Study On The Design, Synthesis And Activity Of Novel Benzimidazole Compounds

Benzimidazole,a heteroaromatic compound with two nitrigon atoms,shows diverse biological acitivities because it is a good bioisoster of guanine residue and other biomolecules.Benzimidazole nucleus is an important pharmacophore in drug discovery.Since it is commonly encountered in drugs that display diversity of pharmacological activities such as antiulcer,antitumoral,antiparasitic, antibacterial,antiviral,anti-inflammatory,and histamine antagonist.Hoechst 33258,a DNA minor groove binder with a bis-benzimidazole structure,shows its excellent cytotoxic activity by selectively binding to DNA and inhibiting topoisomerase I and DNA helicase.Many research articles had reported the derivatives of Hoechst 33258,such as terbenzimidazole,symmetrical bis-benzimidazole.PPIs also have benzimidazole nucleus in their structure.PPIs pretreatment sensitised tumor cell lines to the effect of anti-cancer agents by inhibiting the V-type H⁺-ATPase of tumor cells.Therefore,a new compound,which could more effectively inhibit cancer cells and Hp,was produced by combining the pharmacophores of Hoechst 33258 and PPIs.According to the overlapping pharmacophores of the methodology of design for new drug with multiple ligands,we designed a series of novel bis-benzimidazole compounds with cytotoxic activity and sensitizing effect,which were linked by some species of linkers and were produced by combining the pharmacophores of Hoechst 33258 and PPIs.28 novel bis-benzimidazole compounds were synthesized,which were linked by 1,3-propanediol,1,4-butanediol and 1,6-hexanediol.Their structures were confirmed by LC-MS and ¹H-NMR.In vitro anti-proliferation of tumor cell lines,most compounds were effective,especially,BP2 showed its cytotoxic activity on IC₅₀μM level.We still need to optimize these structures for further studies.Anti-secretory tests in histamine-induced rat model are being used to screen lead compounds from our bis-benzimidazoles.