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)

Etify A Bakhite; Shaaban Kamel Mohamed; Chin-Hung Lai; Karthikeyan Subramani; Islam S Marae; Suzan Abuelhassan; Abdelhamid A E Soliman; Mohamed S K Youssef; Hatem A Abuelizz; Joel T Mague; Rashad Al-Salahi; Youness El Bakri

doi:10.1021/acsomega.4c03208

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)

ACS Omega. 2024 Jul 1;9(28):30751-30770. doi: 10.1021/acsomega.4c03208. eCollection 2024 Jul 16.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, Assiut University, Assiut 71516, Egypt.
² Chemistry and Environmental Division, Manchester Metropolitan University, Manchester M1 5GD, England.
³ Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
⁴ Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung 40241, Taiwan.
⁵ Department of Medical Education, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
⁶ Center for Healthcare Advancement, Innovation and Research, Vellore Institute of Technology University, Chennai Campus, Chennai 600127, India.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁸ Department of Chemistry, Tulane University, New Orleans, Louisiana 70118, United States.
⁹ Department of Theoretical and Applied Chemistry, South Ural State University, Lenin prospect 76, Chelyabinsk 454080, Russian Federation.

Abstract

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.