Design, synthesis and biological evaluation of pyrazoline derivatives for antidepressant activity

Abstrakt

Pyrazolines constitute a class of privileged scaffolds in modern medicinal chemistry, particularly as central nervous system-active agents, and several pyrazoline-based drugs are used to treat various neurological disorders. In the present study, a series of pyrazoline derivatives bearing different substituents at the 2- and 4-positions were subjected to molecular docking against the human serotonin transporter (PDB ID: 5I6X). Based on the docking results, selected Mannich bases of 3-(heteroaryl)-5-(4-substituted aryl)-1-phenyl-4,5-dihydro-1H-pyrazoles were prioritized for synthesis using substituted anilines and formaldehyde. Reaction progress was monitored by thin-layer chromatography (TLC). Structural characterization of the synthesized compounds was performed using IR, 1H NMR, and 13C NMR spectroscopy. Acute toxicity studies were conducted in accordance with OECD guideline No. 425 to determine the LD₅₀ values. The antidepressant activity of the synthesized compounds was evaluated using the forced swim test, and statistical analysis was carried out by one-way ANOVA followed by Dunnett’s post hoc test.
Compound 2b (percentage change in immobility time: -37.51%), followed by compound 2f (-36.91%) and compound 2e (-36.64%), exhibited significant antidepressant activity at a dose of 10 mg/kg, as evidenced by a marked reduction in immobility time. Structure–activity relationship analysis indicated that the presence of electron-withdrawing groups, such as chloro, bromo, and nitro substituents, at the 2- and/or 4-positions of the phenyl ring at the 5-position of the pyrazoline moiety, as well as on the aniline side chain, enhanced the antidepressant potential of the compounds.