Synthesis And Antiviral Activities Of A Novel Series Of Benzimidazole Derivatives Bearing A4/5-heterocyclic Substituent

Benzimidazole is a heterocyclic aromatic compound consists ofbenzene and imidazole rings and displays a broad spectrum of biologicalactivity including antiviral，antifungicide，anti-inflammatory effects. Somebenzimidazole compounds have shown good effects in therapeutic areas forhypertension and ulcer． Therefore benzimidazole compounds haveattracted considerable attention of the pharmaceutical industry．Somecompounds containing oxadiazole,1,3,4-thiadiazole,1,2,4-triazole groupsalso have been broadly used as fungicide，insecticide，herbicide，growthhormone，etc．In our previous work, a series of2-pyridyl-1H-benzimidazole-4-carboxamide derivatives were synthesized and screened, and thesecompounds were indentified as modest inhibitors of Coxsakie virus B3. Inview of these observation and realizing the inforcement of many biologicalactivities by means of combining these heterocycles，we designed and synthesized2-substituted benzimidazole compounds incorporating withheterocyclic rings as oxadiazole,1,3,4-thiadiazole and1,2,4-triazole at the4/5-position in effort to enhance their biological activity．A series ofdesired benzimidazole derivatives were synthesized and their biologicalactivity against anti enteroviruses were tested．The structures of all thesynthesized compounds were confirmed by elemental analysis and1HNMR spectroscopy．2,3/3,4-diaminobenzoic acid as the raw material, the first synthesis of aseries of2-substituted-1H-benzimidazole-4/5-carboxylic acid compoundswere synthesized. Substituents include:2-pyridyl,3-pyridyl,4-pyridyl,phenyl, and ethoxy. Then a series of new benzmidazole derivatives weredesigned based on the2-substituent-1H-benzimidazole-4/5-carboxylicacids and synthesized. Inhibitory activities of these benzimidazolederivatives were tested against CVB3and CVB6. These benzimidazolederivatives were found to exhibit excellent inhibitory activities.Compound5d displayed optimal antiviral activities and selectivitiesagainst all the2kinds of enteroviruses. SAR (Structure and ActivityRelationship) was studied. It can be concluded that compounds with2-pyridyl,3-pyridyl and4-pyridyl at the benzimidzole ring2positionexpressed better antiviral activities against enteroviruses than the compounds with phenyl and ethoxy at the benzimidazole ring2position;the activities of1,3,4-oxadiazole derivatives were better than those ofthiadiazole and triazole derivatives; benzimidazole compounds with aheterocyclic ring at the5position have better biological activity againstenteroviruses than benzimidazole compounds with a heterocyclic ring atthe4position.It was also found that a compound seemed to be effective against othervirus if it was effective against one virus of the same family. Hopefully,these benzimidazole derivatives bearing heterocyclic rings might beeffective against all the enteroviruses, even the entire pico-RNA-virusfamily, because of the similar inhibitory mechanism.The reaction processes were also optimized. As a result of theoptimization, the procedures were simplified and the yields were improved.