Triazole Derivatives As Inotropic Agents;Chalcone And Aminoguanidine Derivatives As Anti-bacterial And Anti-inflammatory Agents.Design,Synthesis And Biological Evaluation

With the frequent occurrence of human chronic heart failure disease,as well as the inflammation induced by clinical bacterial infection appearing constantly,it makes the search for new drugs in the treatment of heart failure,bacterial infection and inflammation become an important topic.According to hybridization and bioisostere strategy,four novel series triazole derivatives were designed and synthesized by combining triadimefon with piperazine and triazole structure in this work.At the same time,the experiments of the negative inotropic activity study and in vitro cytotoxicity evaluation,as well as the mechanism of action research were carried on.The results showed that most of the tested compounds showed stronger negative inotropic activity than that standard drugs metoprolol under the test concentrations.Furthermore,aminoguanidine were fused with a chalcone or chalcone isostere to offer nine novel series target compounds containing aminoguanidine or chalcone structure.The target compounds were preliminary screened for their antimicrobial activity,in vitro anti-inflammatory activity and cytotoxicity,respectively.The molecular docking simulation test about the synthesized compounds was carried on.Most of the synthesized compounds showed potent inhibitory activities against the different bacteria and inflammation,which obviously better than the positive control drug.The structure of target compounds were confirmed by MS and 1H-NMR,part of the compounds was characterized by IR,13C-NMR and HRMS.The researeh of this dissertation could be divided into three chapters as follows:First,four series a total of 39 of triazole structure derivatives were designed,synthesized and evaluated for negative inotropic activity by measuring the left atrium stroke volume in isolated rabbit heart preparations.Results revealed that most of the compounds exhibited good negative inotropic activity,only one compound showed inactive,among which 7h proved to be the most potent with-48.22±1.36%decreased stroke volume(metoprolol:9.74 ± 0.14%)at a concentration of 3×10-5 M,which was 5-fold more potent in its activity than metoprolol and has little effect on experimental animal heart rate.The results of the cytotoxic tests indicated that these series of compounds did not exhibit any remarkable cytotoxicity.The results of mechanism study demonstrate that the negative inotropic effect of compound 7h might be by blocking the myocardial cell calcium ion channels and decreasing the flow of calcium ion in myocardial cells to play its negative inotropic effect as a L-type Ca2+ channel blockers nifedipine.Second,four novel series of chalcone derivatives containing an aminoguanidine or acylhydrazone moiety were designed,synthesized and evaluated in terms of their antibacterial and anti-inflammatory activities.Compounds 4f and 4h exhibited the highest activity of all the compounds synthesized against S.typhimurium 1926 with an MIC value of 1?g/mL,making them 2-fold more potent than gatifloxacin and equipotent to moxifloxacin.Against the Gram-positive strains(S.aureus 503 and S.aureus 209)and Gram-negative E.coli 1924,these two compounds showed equipotent or more potent to the standard drugs gatifloxacin and moxifloxacin with an MIC value of 2?g/mL.Against the fungus C.albicans 7535,compound 4f displayed the strongest potency of all of the compounds synthesized in series 4 with an MIC value of 1?g/mL,which was equal to that of fluconazole.It is noteworthy that compound 4f exhibited the most potent anti-inflammatory activity of all the compounds with an activity of 92.45%,which was higher than those of ibuprofen(87.36%)and indomethacin(89.38%).In addition,the results of in vitro cytotoxicity showed that the tested target compounds showed slight cytotoxicity to the tested tumor cells and normal cells,but did not affect the growth of cell strains.Molecular docking study showed that the antimicrobial activity of the synthesized chalcone derivatives might display their effcts by inhibiting DNA gyrase.Third,five novel series of aminoguanidine derivatives were designed,synthesized and evaluated for their anti-inflammatory activities.The target compound 23a-j and 24a-b were also evaluated for their antimicrobial activity.The results of antibacterial experiment revealed that most of the tested target compounds exhibited good inhibitory potency against tested strains,among which compound 23h exhibited good poteney against S.aureus 4220,Streptococcus mutans 3065 and fungus(Candida albicans 7535)with an MIC value of 2?g/mL,which is weaker than the standard drugs.In addition,compound 23h exhibited the most potent anti-inflammatory activity of all the compounds with an activity of 99.10%,which was higher than those of ibuprofen(87.36%)and indomethacin(89.38%).The results of in vitro cytotoxicity showed that the tested target compounds showed slight cytotoxicity to the tested tumor cells and normal cells.The work might provide an experimental basis for the development of new candidates with potent negative inotropic activities and antibacterial activities and anti-inflammatory activities for the clinical treatment,respectively.