Synthesis, Crystal Structure, Hirshfeld Surface Analysis, and Computational Approach of a New Pyrazolo[3,4-<i>g</i>]isoquinoline Derivative as Potent against Leucine-Rich Repeat Kinase 2 (LRRK2)

Abstract

Ethyl-2-((8-cyano-3,5,9a-trimethyl-1-(4-oxo-4,5-dihydrothiazol-2-yl)-4-phenyl-3a,4,9,9a-tetrahydro-1<i>H</i>-pyrazolo[3,4-<i>g</i>]isoquinolin-7-yl)thio)acetate (<b>5</b>) 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 <b>5</b> 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 <b>5</b> 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 <b>5</b> and was further subjected to molecular docking studies, molecular dynamics, and ADMET analysis to probe potential drug candidacy.