Ethyl-2-((8-cyano-3,5,9a-trimethyl-1-(4-oxo-4,5-dihydrothiazol-2-yl)-4-phenyl-3a,4,9,9a-tetrahydro-1H-pyrazolo[3,4-g]isoquinolin-7-yl)thio)acetate (5) was synthesized, and its structure was characterized by IR, MS, and NMR (¹H and ¹³C) and verified by a single-crystal X-ray structure determination. Compound 5 adopts a “pincer” conformation. In the crystal, the hydrogen bonds of −H···O, C–H···O, and O–H···S form thick layers of molecules that are parallel to (101). The layers are linked by C–H···π(ring) interactions. The Hirshfeld surface analysis shows that intermolecular hydrogen bonding plays a more important role than both intramolecular hydrogen bonding and π···π stacking in the crystal. The intramolecular noncovalent interactions in 5 were studied by QTAIM, NCI, and DFT-NBO calculations. Based on structural activity relationship studies, leucine-rich repeat kinase 2 (LRRK2) was found to bind 5 and was further subjected to molecular docking studies, molecular dynamics, and ADMET analysis to probe potential drug candidacy.

中文翻译：

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一种有效对抗富含亮氨酸重复激酶 2 (LRRK2) 的新型吡唑并[3,4-g]异喹啉衍生物的合成、晶体结构、赫什菲尔德表面分析和计算方法


乙基-2-((8-氰基-3,5,9a-三甲基-1-(4-氧代-4,5-二氢噻唑-2-基)-4-苯基-3a,4,9,9a-四氢-合成了1 H-吡唑并[3,4- g ]异喹啉-7-基）硫代）乙酸酯（ 5 ），并通过IR、MS和NMR（ ¹ H和¹³ C）对其结构进行了表征，并通过单次验证验证了其结构。 -晶体X射线结构测定。化合物5采用“钳子”构象。在晶体中，-H···O、C-H···O和O-H···S的氢键形成平行于(101)的厚分子层。这些层通过 C–H·π（环）相互作用连接。赫什菲尔德表面分析表明，晶体中分子间氢键比分子内氢键和π·π堆积更重要。通过QTAIM、NCI和DFT-NBO计算研究了5中的分子内非共价相互作用。基于结构活性关系研究，发现富含亮氨酸的重复激酶2（LRRK2）与5结合，并进一步进行分子对接研究、分子动力学和ADMET分析以探索潜在的候选药物。