Synthesis And Atrial Inotropic RegμLation And Anti-inflammatory Activities Research Of Triazole Compounds

This article includes two parts:first, we summarized the structural features of the compounds which can act on myocardium according to previous research works, and synthesized 4 series derivatives,6-substituted-[1,2,4]triazolo[3,4-a]phthalazines (compound 15),7-substituted-4,5-dihydro-[1,2,4]oxadiazolo[4,3-α]quinolin-l-ones (compound 16), 7-substituted-triazolo-[3,4-b]benzo[d]Thiazoles (compound 17) and 5-substituted-[1,2,4] triazolo[4,3-c]quinazolin-3-amines (compound 18), based on the lead compound 6-substituted-[1,2,4] triazolo[3,4-a] phthalazines (compound 14), and researched the inotropic effects of 74 compounds on atrium sinistrum. The structure-activity relationship was discussed according to the pharmacological activities. The resμLts showed that in the synthesis of four series of compounds, some had positive effect on the atrium, and others had a negative regμLatory role, especially the most active compound 6-(1-Phenylethoxy)-[1,2,4]triazolo[3,4-a]phthalazine (compound 15m) in 15 series, which decreased the heart stroke volume more than 95% at 50 μmol/L and had specificity in inhibition on myocardial cells in further research. It was expected to be a tool medicine for cardiac research.Then, three types of derivatives were designed and synthesized based on the combination principles and evaluated the anti-inflammatory activity. ResμLts exhibited that some compounds showed better anti-inflammatory activity, especially 9-(4-phenyl)-5,8,9,10-four-hydrogen-hybrid-4H-7-oxygen-2,3,9,11b-four-nitrogen-heterocyclic-pentadiene[a] anthracene (compound 6d), which showed better anti-inflammatory activity in both oral and abdominal than ibuprofen in the same conditions. 6d still kept good anti-inflammatory activity, even increased, when make it into hydrochloride salt. The cytotoxic test of 6d salt proved that it had no toxic effect on RAW264.7 cells at 0 to 50 μg/mL concentrations. In LPS induced RAW264.7 cells secrete factors the influence of the synthetic study of compound 6d can significantly reduce the concentration of IL-6 and TNF-alpha of supernatant on the cell. In the research on mechanism of compound 6d showed that compound anti-inflammatory effect of 6d maybe relate with ERK1/2, P38 lightning/MAPK and NF-κB signaling pathways.In mouse models of LPS-induced acute lung injury (ALI), compound 6d can significantly reduce the concentration of TNF alpha and the of IL-6 in the BALF, meanwhile reduce the W/D ratio of lung tissue. ResμLts of gap-associated proteins in ERK1/2 and P38MAPK signailing pathways are consistant with cell test. Histopathology of lung tissue also indicated better protective effect from lung injury. Above all:new synthesized compounds exhibited strong anti-inflammatory activity, the derivatives of the discovery has provided the basis for the future development of anti-inflammatory drugs.