Synthesis and characterization of new 5,5′-dimethyl- and 5,5′-diphenylhydantoin-conjugated hemorphin derivatives designed as potential anticonvulsant agents

Herein, the synthesis and characterization of some novel N-modified hybrid analogues of hemorphins containing a C-5 substituted hydantoin residue as potential anticonvulsants and for the blockade of sodium channels are presented.

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

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.

Synthesis of Novel Triazolyl/Oxadiazolyl/Thiadiazolyl-Piperazine as Potential Anticonvulsant Agents

Reaction of piperazine with chloroacetylchloride in dry acetone yield compound 1 , which on reaction with hydrazine hydrate yielded compound 2, which was further reacted with various substituted phenylisothiocyanates in absolute alcohol to afford compounds 3–8 i. e. 2-(carbazolylacetyl)-N-(substitutedphenyl)-hydrazinepiperazinothioamides. Compounds 3–8 on reaction with aqueous NaOH, ethanolic NaOH and conc. H2SO4 afford triazoles 9–14, oxadiazoles 15–20 and thiadiazoles 21–26 respectively. Twenty four newly synthesized compounds were evaluated for their anticonvulsant activity and acute toxicity. The structures of these compounds were established on the basis of analytical and spectral data.