Studies On The Structure-activity-relationship Of2-alkoxycarbonyl-4-phenyl(fluorophenyl)-1,5-benzothiazepine

1,5-benzothiazepines is a kind of compound which has important drug activities. Studiesshow that1,5-benzothiazepine derivatives have effects on antifungal, antianxiety,antispasmodic, antihypertensive etc. Therefor, the study of the synthesis, structure and drugactivity of these compounds have became a hot t research field.Our laboratory has engaged in the investigation of the design, synthesis1,5-benzothiazepine derivatives and the research of their antimicrobial activities.andsynthesized a series of novel structure1,5-benzothiazepine derivatives. It found that some ofthe compounds such as2-ethoxycarbonyl-4-phenyl-1,5-benzothiazepine5a(Figure2) and2-alkoxycarbonyl-4-fluorophenyl-1,5-benzothiazepine A、B、C、D、E、F(Figure3) havestrong antimicrobial activity. In order to investigate the key structural of those derivative whohas high antifungal activity, we have synthesized a series of new1,5-benzothiazepinederivatives based on5a and A~F through remove or change the alkoxycarbonyl group,reduction of the double bond C=N, replace S atoms in the heterocyclic ring by other atom. Byevaluated the antifungal activity of these new compounds, the contribution of atoms orfunctional groups to the inhibiting fungal activity of the compound5a, A~F have beeninvestigated to explore the relationship between the structure and activity.The thesis consists of two parts. In the first part, we take the high activity compound5aas the object of research to study the structure-activity relationship. The study includes:1、Synthesis: A a series of novel4-phenyl-1,5-benzothiazepine5b~5j are synthesizedby four-step reaction such as Friede-Crafts acylation reaction,ect, where different substitutedbenzene1, glutaric anhydride, alcohol,2-aminobenzenethiol are used for the raw materials.6a~6e and7a~7f were given respectively by5a~5f thought oxidation or reduction.2、Evaluat the antibacterial activity of compounds synthesized by inhibition zonemethod. By testing the antibacterial activity of the new compounds, we found that the activityof most compounds was low or even disappear. The result shows that the three active groupsincluding2-alkoxycarbonyl,4-para-substituted phenyl and C=N play an important role for theinhibition of fungal, and role of S atoms need to be further identified. The good inhibitory effect on cryptococcus of compound5b shows that compounds whose para-substituted groupof4-phenyl is hydrogen or fluoride have good antifungal activity.3、We have evaluated the antibacterial activity of compounds who have high activityfurther by testing the concentration gradient, minimum inhibitory concentration, andminimum bactericidal concentration of these compounds.In the second part, we take the high activity compound A~F as the object of research tostudy the structure-activity relationship. The study includes:1、Synthesis：（i）A a series of novel1,5-benzothiazepine13a~13c are synthesized byseven-step reaction such as wittig reaction and Michael addition reaction and so on, whereacetophenone8, cupric bromide, paraformaldehyde and2-aminobenzenethiol are used for theraw materials.(ii) Phenyl ethyl ketone and aldehyde acid react with different alcohols to getthe α,β-unsaturated ketone14a~14c by aldol condensation and esterification reaction.14a~14c react with the2-aminobenzenethiol to formed1,5-benzothiazepine16a~16f, with the2-aminophenol to formed1,5-benzoxazepines17a~17f and with the o-phenylenediamine toget1,5-benzodiazepine18a~18f.2、Evaluat the antibacterial activity of compounds synthesized. By testing theantibacterial activity of the new compounds,we found that the activity of most compoundswas low or even disappear which indicated that2-ester groups, C=N and S atoms have amajor effect on the antibacterial activity of compounds.3、In the synthesis of1,5-benzoxazepines and1,5-benzodiazepine procedure, we havedelved into the reaction conditions from catalyst, solvent, and temperature and foundd asimple and convenient synthetic route.