The Studies On Green Synthesis And Structure-activity Relationship Of Functionalized 1,5-benzodiazepines With Acyl,Ester And Carboxyl Groups

Benzodiazepines are a class of organic molecules with a wide range of biological activities and pharmacological functions.Among them,1,5-benzodiazepine is often used as anxiolytic drugs and anticonvulsants.In recent years,the 1,5-benzodiazepines have been found to have excellent antibacterial activity.Therefore,the design and synthesis of1,5-benzodiazepines with high bioactivity have attracted more and more researchers.The our group has long been committed to the design,synthesis of 1,5-benzodiazepine derivatives and research of structure-activity relationship.The active 1,5-benzodiazepine as the basic structure,by introducing active groups such as ester groups,carboxyl groups,acyl groups,aromatic heterocyclic rings,lactone rings,changing the ester chain and changing the electrical properties of the substituents,hundreds of 1,5-benzodiazepine derivatives have been successfully synthesized by various chemical processes.However,compounds containing free acyl substituents on the seven-membered ring have not been synthesized and reported.Thus,a series of 3-acyl-1,5-benzodiazepines have been designed and synthesized in this paper.Meanwhile,we tried to introduce several functional groups into the same compound molecule to synthesize 15 kinds of 1,5-benzodiazepines substituted by bifunctional groups containing ester group and acyl group,carboxyl group and acyl group simultaneously.Additionally,the antimicrobial activity of the compounds was tested and the structure-activity relationship of these compounds was summarized.Based on the preliminary work of our group,the structure-activity relationship of the 1,5-benzodiazepines synthesized in various structures was further explored.The main work of this paper is as follows:1.2-aryl-3-acetyl-1,5-benzodiazepines was synthesized from simple and readily available inputs including o-phenylenediamine,aromatic aldehyde and 3-butyn-2-one in the presence of a catalytic amount of CeCl3·7H2O in ethanol at ambient temperature in excellent yields by a green one-pot reaction.When substituted o-phenylenediamine was used as the starting material,26 single isomers IV and V were synthesized by two different routes in two-step reaction to enhance the chemical selectivity of the reaction.Antibacterial tests in vitro were performed on the synthesized compounds.The results showed that the compoundssubstituted by different aromatic rings showed excellent selectivity to different strains,and their structure-activity relationship was studied preliminarily.2.The substituted o-phenylenediamine,aromatic aldehyde and Eyhyl pyruvate(Ethyl glyoxalate and Glyoxylic acid)as valuable substrates,we successfully synthesized 15double-carbonyl 1,5-benzodiazepines bearing free ester(or free carboxyl)and free acyl on the seven-membered ring in the presence of CeCl3·7H2O in ethanol at ambient temperature by multi-step reaction.And The first step reaction was without any catalyst,the second step reaction was catalyzed by CeCl3·7H2O.The reaction has a milder conditions,shorter reaction time,high yield etc.The target compounds were tested for antibacterial activity.The results showed that the compounds showed strong selectivity to the tested strains,that is,only showed a certain inhibitory effect on S.aureus.And its structure-activity relationship was studied.3.In this paper,the structure-activity relationship of synthesized all the1,5-benzodiazepines compounds in our group was summarized from the micro and macro perspectives.On the basis of this,the structure-activity relationship of the active3-ester-1,5-benzodiazepines and 1,5-benzodiazepines with a five-membered ring lactone was further explored.Then we established the monadic and binary equations.The relationship between the antibacterial activity of the compounds with orbital energies of the front orbits or the contributions of the HOMO orbitals of N7 and N11 was revealed by the monadic and binary equations.