Studies On The Synthesis And Antimicrobial Activity Of 1, 5-benzothiazepines Containing Amide Groups

Benzozepines are important heterocyclic compounds which have wide range of biological activities.Some of them have been clinically used as antianxiety,hypnotic and cardiovascular drugs,therefore,investigation of new kind of benzozepines with unique citivities has became an attractive target for many researchers.1,5-benzothiazepines are a important group of benzozepines.Over the past decade,there has been deep and systematical research on the field of exploring active 1,5-benzothiazepines in our laborary.More recently,a series of ester groups substituted 1,5-benzothiazepines were synthesized by us and showed remarkable antifungal activity against C.albicans.Ester and amide groups are isosterisms each other,so replacement of the ester groups with amide groups may be useful for finding new 1,5-benzothiazepines with unique antimicrobial activity. In order to find more antimicrobial new 1,5-benzothiazepines,we designed and synthesized a new kind of 1,5-benzothiazepines with different amide groups.The structures of these compounds were determined by IR,~1H NMR,MS and elemental analysis.The synthesized compounds were evaluated for their antimicrobial activity against C.albicans,S.epidermidis and S.aureus,and Escherichia.coli.and were investigated for the structure-activity relationships preliminarily.We also studied the synthesis reaction condation deeply.All of the studies will be important for further expanding the application of 1,5-benzothia-zepines in pharmacy and development of new antifungal medicines.This thesis includes the major parts:1.In this paper,three series of new 1,5-benzothiazepines bearing amide groups(14 compounds) were synthesized from aromatic hydrocarbon,succinic anhydride and 2-amino-thiophenol by the reaction of Friede-Crafts acylation,substitution,elimination,cyclo-addition and so on.The structures of all the compounds were established by IR,~1H NMR,MS and elemental analysis.We also studied about the mechanism and condition of various reaction deeply.2.We have carried out a detailed study on the synthesis method of the amides about 1,4-dicarbonyl compounds including the methods of benzotriazole,1,3-dicyclohexyl carbodiimide(DCC),mixed anhydride and acid chloride.The best synthetic method of those compounds were found.3.The antibacterial activity of the 2-amide-4-aryl-1,5-benzothiazepine compounds was tested in vivo using filter paper method.The results indicated that:Most of the benzothiazepine compounds have perfect inhibition against fungus(C.albicans),expecially for the compounds with secondary amine amides.The primary aliphatic amine amide substituted benzothiazepines have better antibacterial effects than those containing aromatic amide;ester substituted benzothiazepines were also better than the amide substituted benzothiazepines.in antifungus activity.The results also showed that most of the synthesized compounds have certain inhibition against S.aureus and S.epidermids,but have no significant inhibition against Escherichia.coli.It can be seen that this type of 1,5-benzothiazepines have significantly antibacterial activity for the fungi.All of the study results will be important for screening for active substances and designing drugs.