Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia; Research Group in Development of Materials and Products, CDT ASTIN SENA, Calle 52 # 2Bis-15, Cali, Colombia.
Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia.
Comput Biol Chem. 2018 Jun;74:218-229. doi: 10.1016/j.compbiolchem.2018.03.001. Epub 2018 Mar 7.
Given the wide spectrum of biological uses of pyrazolo[1,5-c]quinazoline and spiro-quinazoline derivatives as anticancer, anti-inflammatory analgesic agents, and their therapeutic applications in neurodegenerative disorders, it is compulsory to find easy, efficient, and simple methods to obtain and chemically diversify these families of compounds, thereby improving their biological applications. In this paper, we report the design and eco-friendly two-step synthesis of novel, fused spiro-pyrazolo[1,5-c]quinazoline derivatives as cholinesterase inhibitors. In addition, we studied their protein-ligand interactions via molecular docking and MM/GBSA calculations for a further rational design of more potent inhibitors. In first step, 2-(1H-pyrazol-5-yl)anilines were obtained through microwave (MW) assisted solvent-free/catalyst-free conditions and the second step involved the synthesis of the spiro-pyrazolo[1,5-c]quinazolines by a cyclocondensation reaction between 2-(1H-pyrazol-5-yl)anilines and cyclic ketones, or acetophenones, using stirring at room temperature. The compounds were obtained in high purity, good yields (50-97%), and at varying reaction times. The spiro-compounds were evaluated as acetylcholinesterase and butyrylcholinesterase inhibitors (AChEIs/BuChEIs) respectively, and the most potent compound exhibited a moderate AChE inhibitory activity (5f: IC = 84 μM). Molecular docking studies indicated that the binding mode of the compound 5f share common characteristics with the galantamine/donepezil-AChE complexes. Moreover, free binding energy (ΔG) calculations showed a good agreement with the experimental biological activity values. Our theoretical results indicated that halogen bond interactions could be involved with differential potency of these compounds and provide a new starting point to design novel pyrazolo[1,5-c]quinazolines as new anti-Alzheimer agents.
鉴于吡唑并[1,5-c]喹唑啉和螺环喹唑啉衍生物在抗癌、抗炎、镇痛剂方面的广泛生物学用途，以及它们在神经退行性疾病中的治疗应用，找到获得和化学多样化这些化合物家族的简单、高效和简单方法是强制性的，从而提高它们的生物学应用。在本文中，我们报告了新型融合螺吡唑并[1,5-c]喹唑啉衍生物作为胆碱酯酶抑制剂的设计和环保两步合成。此外，我们通过分子对接和 MM/GBSA 计算研究了它们的蛋白质-配体相互作用，以进一步合理设计更有效的抑制剂。在第一步中，通过微波（MW）辅助无溶剂/无催化剂条件获得 2-（1H-吡唑-5-基）苯胺，第二步通过 2-（1H-吡唑-5-基）苯胺与环状酮或苯乙酮之间的环缩合反应合成螺吡唑并[1,5-c]喹唑啉，使用室温搅拌。化合物以高纯度、良好的收率（50-97%）和不同的反应时间获得。螺环化合物分别作为乙酰胆碱酯酶和丁酰胆碱酯酶抑制剂（AChEIs/BuChEIs）进行评估，最有效的化合物表现出中等的乙酰胆碱酯酶抑制活性（5f：IC=84µM）。分子对接研究表明，化合物 5f 的结合模式与加兰他敏/多奈哌齐-AChE 复合物具有共同特征。此外，自由结合能（ΔG）计算与实验生物活性值吻合良好。我们的理论结果表明，卤键相互作用可能与这些化合物的差异效力有关，并为设计新型吡唑并[1,5-c]喹唑啉作为新型抗阿尔茨海默病药物提供了新的起点。
