Synthesis, Antidepressant-like and Anxiolytic-like Effects of Novel Thiadiazole Derivatives: Behavioral Assessment and Mechanistic Investigation

Background/Objectives: Based on the central nervous system-related activity potential of 1,3,4-thiadiazole derivatives, novel 1,3,4-thiadiazole compounds were synthesized, and their possible antidepressant-like and anxiolytic-like effects were investigated. Methods: The chemical structures of the compounds were elucidated using several spectroscopic techniques. Antidepressant-like effects of compounds were evaluated using the tail suspension and the modified forced swimming tests, while anxiolytic-like effects were assessed using the hole board, elevated plus maze, and open field tests in male Balb/c mice. Motor activities of the animals were examined using the activity-meter device. Mechanistic and computational in silico studies were also performed. Results: The results demonstrated that compounds 4e–4i exhibited antidepressant-like effects, whereas only compound 4e showed an anxiolytic-like effect. None of the compounds produced significant alterations in motor activities of animals, indicating that the observed behavioral effects were specific. The antidepressant-like effects of compounds 4e–4i were abolished by p-chlorophenylalanine methyl ester (PCPA) and α-methyl-para-tyrosine methyl ester (AMPT) pre-administration indicating that the antidepressant-like effects of these test compounds are related to both serotonergic and catecholaminergic mechanisms. Furthermore, the anxiolytic-like effect of compound 4e was reversed by flumazenil and NAN-190 pre-administrations, indicating the participation of the GABA-A benzodiazepine receptor complex and 5-HT1A receptors in its pharmacological activity. Computational in silico studies revealed that compounds have good ADME profiles; compounds 4e–4i interact with the serotonin transporter; compound 4e shows affinity for GABA-A and 5-HT1A receptors; and all interactions remain stable under dynamic conditions. Conclusions: These findings supported the previous papers reporting the antidepressant-like and anxiolytic-like effects of 1,3,4-thiadiazole derivatives.