IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE (QUINOLINE) DERIVATIVES

Abstract

To find biological activity among easily available 2-[(4S,4’S/4R,4’R)-2’,5’-dioxo-2,3,5,6,7,8-hexahydro-1H-spiro[acridine-4,3’-pyrrolidin]-4’-yl]-N-aryl-acetamide, (4S/4R)-4-[(3R/3S)-1-(2-aryl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile, (3S/4R)-3-[(3R/4S)-9-chloroacridine(quinoline)-4-yl]-1-N-aryl)pyrrolidine-2,5-diones. Methods: Organic synthesis, spectral methods, and molecular docking. We investigated by molecular docking the potential biological activity of previously synthesized compounds containing acridine and pyrrolidine-2,5-diones fragments in their structure, as well as synthesized in this work N’-hydroxy-1,2,3,4,5,6,7,8-octahydroacridine-4-carboximidamide. Based on the literature data, 3 directions of searching for the biological activity of the synthesized compounds have been chosen: cholinesterase inhibitors, anti-inflammatory, and anticonvulsant agents. As inhibitors of acetylcholinesterase and butylcholinesterase, substances with good binding free energy and hydrogen bonds with the desired amino acid residues of the Glu-His-Ser triad have been found among the tested compounds. The indicators of synthesized products have exceeded the literature data. The docking data for anti-inflammatory activity has revealed compounds with values above the docking data of the reference drugs - celecoxib and indomethacin. The compounds tested have shown moderate activity as anticonvulsant agents. 3-(7-bromo-9-chloro-1,2,3,4-tetrahydroacridin-4-yl)-1-(3-nitrophenyl)pyrrolidine-2,5-dione is potentially promising as an acetylcholinesterase inhibitor due to its high binding free energy (-13.7 kcal/mol) and hydrogen bonds with two amino acid residues Ser200, His440. Compound (4S/4R)-4-[(3R/3S)-1-(3-nitrophenyl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile has proved to be the best as an anti-inflammatory agent. The presence of a pyrrolidine-2,5-diones fragment increases the indicators of the biological activity of the synthesized compounds in comparison with just acridine derivatives.