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
; 9(28): 30751-30770, 2024 Jul 16.
Article
em En
| MEDLINE
| ID: mdl-39035914
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.
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MEDLINE
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En
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ACS Omega
Ano de publicação:
2024
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Article
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