Exploring N-heterocyclic linked novel hybrid chalcone derivatives: synthesis, characterization, evaluation of...

In the search for novel antidepressant agents, twelve novel nitrogen-containing heterocycle-linked chalcone derivatives have been synthesized and comprehensively characterized using FT-IR, ¹H NMR, ¹³C NMR, and Mass spectral methods. The synthetic strategy involves the preparation and optimization of reaction conditions for obtaining 4-carbazole-, indole-, and pyrrole-linked acetophenones, which were subsequently coupled with pyrazole aldehydes bearing piperidine, morpholine, benzotriazole, and imidazole ring systems. In vivo antidepressant activity of the compounds was evaluated using the Tail Suspension Test (TST) and Forced Swim Test (FST). Chalcone derivatives with a benzo[d][1,2,3]triazol-1-yl substituent exhibited significant reductions in immobility times, indicating enhanced antidepressant activity. Chalcone derivatives with piperidin-1-yl and morpholino groups demonstrated relatively lower activity. Molecular docking studies against the human serotonin transporter (hSERT) (PDB code: 5I6X) revealed that the chalcone derivatives exhibited excellent binding affinity (average docking score: -8.540, binding energy: -60.044 kcal mol^-1) through favorable van der Waals, electrostatic, and hydrogen bonding interactions (only for 13b) within the active site. The binding interaction of compound 13b was particularly strong, with a Glide docking score of -9.120 and binding energy of -65.454 kcal mol^-1, highlighting the contribution of both π-π stacking and hydrogen bonding interactions. Chalcone derivatives showed low acute oral toxicity (LD₅₀ > 2000 mg kg^-1, category 5) in female Swiss albino mice per OECD 423 guidelines, with no mortality or adverse effects at 300 and 2000 mg kg^-1, and normal body weight gain over 14 days. These findings underscore the potential of benzo[d][1,2,3]triazol-1-yl-based chalcone derivatives as promising antidepressant agents with a favorable safety profile. Density Functional Theory (DFT) analysis was performed on the most active compound, 13c, to gain insights into its structural and electronic properties. Additionally, ADME (Absorption, Distribution, Metabolism, and Excretion) profiling of the synthesized compounds indicated favorable drug-like characteristics and balanced pharmacokinetic profiles, supporting their potential as promising candidates for further pharmaceutical development.