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

Abstract

5,4,9,isoquinolin-7-yl)thio)acetate (5) was synthesized, and its structure was characterized by IR, MS, and NMR ( 1 H and 13 C) and verified by a single-crystal X-ray structure determination. Compound 5 adopts a "pincer" conformation. In the crystal, the hydrogen bonds ofthick 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.