Crystal structure, Hirshfeld surface analysis, and molecular dynamics simulations of two isostructural N-propargyl-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolines

• Published in: Journal of molecular structure 2022-04, Vol.1254, p.132280, Article 132280
• Main Authors: Güiza, Fausto M., Rodríguez-Núñez, Yeray A., Ramírez, David, Romero Bohórquez, Arnold R., Henao, José Antonio, Toro, Robert A., Delgado, José Miguel, Díaz de Delgado, Graciela
• Format: Article
• Language: English
• Subjects: Cationic Povarov reaction; Crystal structure; Molecular dynamics simulations; Monoamine oxidase B inhibitors; N-propargylamines; Tetrahydroquinoline
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2021.132280

•One-pot cationic Povarov reaction produced two new N-propargyl tetrahydroquinolines.•Single crystal X-ray analysis showed they are isostructural.•H···H, H··;·O, H···π, and H···Cl interactions dominate the crystal packing.•The interaction with monoamine oxidase B was studied by molecular dynamics simulation.•The compounds show similarity with rasagiline, used to treat Parkinson's disease. Two new N-propargyl-4-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinoline derivatives (4a and 4b), have been efficiently prepared through a one-pot InCl3-catalyzed cationic Povarov reaction between N-propargylanilines (1a and 1b), formaldehyde (2) and N-vinyl-pyrrolidin-2-one (3). These compounds were characterized by ATR-FTIR spectroscopy, 1H/13C NMR spectroscopy, ESI-IT mass spectrometry, and by single-crystal X-ray diffraction. N-propargyl-6-methyl-4-(2′-oxopyrrolidin-1′-yl)-1,2,3,4-tetrahydroquinoline (4a) and N-propargyl-6-chloro-4-(2′-oxopyrrolidin-1′-yl)-1,2,3,4-tetrahydroquinoline (4b) are isostructural and crystallize in space group P21/c. The crystal structures are characterized by inversion-related interpenetrated helices along the b-axis that form columns along the c-axis. C—H···O, C—H···C, and C—H···π(aryl) for 4a and C—H···O, C—H···Cl, and C—H···π(aryl) for 4b interactions occur within the columns which are connected by C—H···π(propargyl) interactions. These features were further visualized by Hirshfeld surface analysis and energy frameworks calculations and evaluated by the EXY enrichment ratio. Molecular dynamics simulations show that these compounds are promising monoamine oxidase B (MAO‐B) inhibitors, since they interact with MAO-B in a similar manner as rasagiline, a drug commonly used in the treatment of Parkinson's and Alzheimer's diseases. [Display omitted] Two new isostructural N-propargyl tetrahydroquinolines were prepared via a one-pot InCl3-catalyzed cationic Povarov reaction and their crystal structures were determined. Molecular dynamics simulations were carried out and the behavior is compared to that of rasagiline, a monoamine oxidase B (MAO-B) enzyme inhibitor drug which also carries the N-propargyl group.