We described here our results on the use of thiourea as a ligand in the copper catalysed azide-alkyne cycloaddition (CuAAC) of 2-azidobenzaldheyde with alkynes. Reactions were performed reacting 2-azidobenzaldheyde with a range of terminal alkynes using 10 mol% of copper iodide as a catalyst, 20 mol% of thiourea as a ligand, triethylamine as base, DMSO as solvent at 100 °C under nitrogen atmosphere. The corresponding 2-(1 H -1,2,3-triazoyl)-benzaldehydes (2-TBH) were obtained in moderated to excellent yields and according our experiments, the use of thiourea decreases the formation of side products. The obtained compounds were screened for their binding affinity with multiple therapeutic targets of AD by molecular docking: β-secretase (BACE), glycogen synthase kinase (GSK-3β) and acetylcholinesterase (AChE). The three compounds with highest affinity, 5a , 5b and 5d were selected and evaluated on its antioxidant effect, in view of select the most promising one to perform the in vivo validation . Due the antioxidant potential ally to the affinity with BACE, GSK-3β and AChE, compound 5b was evaluated in a mouse model of AD induced by intracerebroventricular injection of streptozotocin (STZ). Our results indicate that 5b (1mg/kg) treatment during 20 days is able to reverse the cognitive and memory impairment induced by STZ trough the modulation of AChE activity, amyloid cascade and GSK-3β expression.

中文翻译：

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2-（1,2,3-三唑基）苯甲醛作为多功能药物治疗阿尔茨海默氏病的合成，分子对接和初步评估。

我们在这里描述了我们的研究结果，即使用硫脲作为2-叠氮基苯甲醛与炔烃的铜催化叠氮化物-炔烃环加成（CuAAC）的配体。在氮气氛下，在100°C下，使用10 mol％的碘化铜作为催化剂，20 mol％的硫脲作为配体，三乙胺作为碱，DMSO作为溶剂，使2-叠氮基苯甲醛与一定范围的末端炔烃反应。以中等至极高的收率获得了相应的2-（1 H -1,2,3-三唑基）-苯甲醛（2-TBH），根据我们的实验，硫脲的使用减少了副产物的形成。通过分子对接：β-分泌酶（BACE），糖原合酶激酶（GSK-3β）和乙酰胆碱酯酶（AChE），筛选获得的化合物与AD的多个治疗靶点的结合亲和力。考虑到选择最有前途的一种进行体内验证，选择了具有最高亲和力的三种化合物5a，5b和5d并评估了其抗氧化作用。由于抗氧化剂具有与BACE，GSK-3β和AChE亲和力的潜力，因此在由脑室内注射链脲佐菌素（STZ）诱导的AD小鼠模型中评估了化合物5b。我们的结果表明，在20天之内进行5b（1mg / kg）治疗能够逆转STZ通过AChE活性，淀粉样蛋白级联和GSK-3β表达的调节而引起的认知和记忆障碍。在脑室内注射链脲佐菌素（STZ）诱导的AD小鼠模型中评估了化合物5b。我们的结果表明，在20天之内进行5b（1mg / kg）治疗能够逆转STZ通过AChE活性，淀粉样蛋白级联和GSK-3β表达的调节而引起的认知和记忆障碍。在脑室内注射链脲佐菌素（STZ）诱导的AD小鼠模型中评估了化合物5b。我们的结果表明，在20天之内进行5b（1mg / kg）治疗能够逆转STZ通过AChE活性，淀粉样蛋白级联和GSK-3β表达的调节而引起的认知和记忆障碍。