机构地区:[1]贵州医科大学药学院,贵州贵阳550025 [2]贵州省化学合成药物研发利用工程技术研究中心,贵州贵阳550004
出 处:《贵州医科大学学报》2022年第7期752-758,共7页Journal of Guizhou Medical University
基 金:国家自然科学基金(81660348);贵州省卫生健康委科学基金项目(gzwjkj2020-1-206);贵州省普通高等学校青年科技人才成长项目(黔教合KY字〔2022〕246)。
摘 要:目的探讨川芎嗪(TMP)-哒嗪酮耦联化合物的合成及其抗血小板聚集活性。方法以TMP为原料,经溴代得到2-(溴甲基)-3,5,6-三甲基吡嗪备用;以乙酰苯胺为原料,分别经傅-克反应、脱乙酰基、与水合肼环合,最后与2-(溴甲基)-3,5,6-三甲基吡嗪发生取代反应得到目标化合物a;化合物b的合成使用3-(4-甲氧基苯甲酰基)丙酸为原料,分别经脱甲基、与水合肼环合,再与2-(溴甲基)-3,5,6-三甲基吡嗪发生取代反应获得;以三甲基吡嗪和α-酮戊二酸为原料,分别经Minisci反应和水合肼环合得到目标化合物c;家兔心脏取血,离心取上清分别得富血小板血浆(PRP)和贫血小板血浆(PPP,用于调零),PRP分别加目标化合物或阳性药阿司匹林(ASA),以10μmol/L二磷酸腺苷(ADP)或0.5 mmol/L花生四烯酸(AA)为诱导剂,采用born比浊法检测PRP 5 min以内的最大聚集率,计算目标化合物的抗血小板聚集率(AIR)及半数抑制浓度(IC _(50))。结果成功合成3个目标化合物a、b及c,化学结构经HMRS、^(1)H NMR、^(13)C NMR表征及Scifinder检索均为新化合物;目标化合物a、b及c抑制血小板聚集活性大小顺序为c>a>b,且优于TMP和ASA。结论TMP-哒嗪酮耦联合成的3个目标化合物具有较好的抗血小板聚集活性。Objective To investigate the synthesis and antiplatelet aggregation activity of TMP-pyrazinone coupling compound.Methods TMP was used as raw material to obtain 2-(bromomethyl)-3,5,6-trimethylpyrazine by bromination.And acetaniline was used as raw material,the target compound a was obtained by Fourier reaction,deacetylation,cyclization with hydrazine hydrate,and finally substitution reaction with 2-(bromomethyl)-3,5,6-trimethylpyrazine.Compound b was synthesized with 3-(4-methoxy benzoyl)propionic acid as raw material by demethylation,cyclization with hydrazine hydrate respectively,and then with 2-(bromomethyl)-3,5,6-trimethylpyrazine substitution reaction.Trimethylpyrazine andα-ketoglutaric acid were used as raw materials,the target compound c was obtained by Minisci reaction and cyclization of hydrazine hydrate respectively.Anti-platelet aggregation activity was tested by the born turbidimetric method.The platelet-rich plasma(PRP)and platelet-poor plasma(PPP)were taken from rabbit hearts,centrifuged,and PPP was used for zeroing.The positive drug aspirin or target compounds a-c were added to PRP and pre-warmed at 37℃for 3 min,then platelet aggregation was induced with 10μmol/L ADP and 0.5 mmol/L AA as inducing agents respectively.The maximum aggregation rate of platelets within 5 min was recorded with a semi-automatic coagulation analyzer,and the _(50)%inhibitory concentration(IC _(50))was calculated.Results Three target compounds were successfully synthesized,and their chemical structures were characterized by HMRS,^(1)H NMR,and^(13)C NMR,and they were all new compounds searched by Scifinder.The results of in vitro antiplatelet aggregation activity test showed that compounds a-c could better inhibit the platelet aggregation induced by adenosine diphosphate(ADP)and arachidonic acid(AA),which was better than the lead compound TMP and the positive drug aspirin.Conclusion TMP-pyrazinone coupling compounds have good anti-platelet aggregation activity which has the value of further research.
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