Synthesis Of Thiazole Amide Derivatives And Evaluation Of Hemostatic Activities

Thiazoles and benzothiazoles represent a universal scaffold in organic synthesis and medicinal chemistry with optimized pharmacological activity characteristics.The biological activity of such derivatives virtually covers the entire drug range,includes promoting thrombocytosis,reducing high blood pressure,anti-cancer,anti-tumor,anti-inflammatory,anti-fungal and reducing cholesterol,exhibiting excellent activity,less toxicity,good resistance,high bioavailability,diverse administration routes and other beneficial properties.This dissertation focuses on 2-aminothiazole and 2-aminobenzothiazole from the following.Throughout this study,2-aminothiazole and 2-aminobenzothiazole were used as raw materials to introduce amide bonds in the synthesis of 19 amide derivatives.The thiazole amide derivatives were characterized by 1H and 13C nuclear magnetic resonance(NMR),fourier-transform infrared spectroscopy(IR),electron ionization mass spectroscopy(EI-MS)and single crystal diffraction(XRD)to help determine the corresponding structure of each target product.In addition to the four derivatives W5,W6,W7 and W9,the remaining 15 thiazole amide derivatives have never been reported before and therefore,to the best of our knowledge,represent new compounds.Thermogravimetric analysis was used to determine the thermodynamic stability of the thiazole amide derivatives.The results showed that the synthesized target compounds featured a good thermal stability at 100 ? and did not oxidize or decompose at room temperature.Importantly,such characteristics are essential for further physiological and biochemical activity testing.The hemostatic activities of all 19 thiazole amide derivatives were tested to obtain information on the physiological and biochemical activity.Therefore,Therefore,the blood coagulation activities consisting of activated partial thromboplastin time(APTT),prothrombin time(PT),thrombin time(TT)and fibrinogen(FIB),and platelet aggregation activity were measured.Based on the results obtained from blood coagulation activities,the 2-aminothiazole amide derivatives N1,N2,N3 and N10 as well as the 2-aminobenzothiazole amide derivatives W2,W4,W5,W6,W7 and W8 exhibited a significantly higher coagulation activity than the positive control p-aminomethylbenzoic acid.Among all compound species,compound N10 significantly decreased APTT,PT and TT and increased the FIB contents.Compounds W4,W7 and W8 have been shown to significantly decrease the PT and TT and increase the FIB contents;Compound W6 significantly decreased the APTT and TT contents and increased the FIB content;Compound W5 significantly decreased the APTT and PT contents and also decreased the TT content;Compounds N2 and N3 significantly decreased the TT and increased the FIB contents;Compound N1 significantly decreased the PT content and increased the FIB content;Compound W2 significantly decreased APTT content and increased the FIB content.Further studies on platelet aggregation activity indicated that the 2-aminothiazoleamide amide derivative N5(EC50 = 1.869 ?mol/L)and the 2-aminobenzothiazole amide derivative W2(EC50=0.036 ?mol/L)were more efficient in promoting platelet aggregation than the clinically administered hemostatic drug etamsylate(EC50 = 46.22 ?mol/L).In conclusion,the 2-aminobenzothiazole amide derivative W2 may represent a potential lead compound for further biological screening and drug development.Furthermore,the experimental results shown in this paper may facilitate the design of compounds with higher efficacy to serve as hemostatic drugs.Presumably,our results will add physiological and biochemical activity data to the data pool of thiazole derivatives and may also provide further information on the exploitation and utilization of amide compounds containing thiazole as hemostatic agents for the treatment of excessive bleeding during surgery.