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Design, facile synthesis, and evaluation of novel spiro- and pyrazolo[1,5-c]quinazolines as cholinesterase inhibitors: Molecular docking and MM/GBSA studies

化学 喹唑啉 对接(动物) 丁酰胆碱酯酶 组合化学 胆碱酯酶 乙酰胆碱酯酶 立体化学 合理设计 加兰他明 阿切 有机化学 多奈哌齐 纳米技术 药理学 医学 材料科学 护理部 痴呆 疾病 病理
作者
Jaime Gálvez,Stivens Polo,Braulio Insuasty,Margarita Gutiérrez,Daniela Cáceres,Jans Alzate‐Morales,Pedro De‐la‐Torre,Jairo Quiroga
出处
期刊:Computational Biology and Chemistry [Elsevier BV]
卷期号:74: 218-229 被引量:35
标识
DOI:10.1016/j.compbiolchem.2018.03.001
摘要

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: IC50 = 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.
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