Synthesis, antidepressant evaluation and computational insights on substituted pyrazoles as selective MAO-A inhibitors

A series of pyrazole derivatives was designed, synthesized, and characterized spectroscopically. All the synthesized compounds were pharmacologically evaluated by in vitro and in vivo methods for their antidepressant activity. Amongst, VK16 and VK19 were the most potent inhibitors of the MAO-A enzyme with IC₅₀ values of 0.06 ± 0.017 μM and 0.09 ± 0.019 μM, respectively, showing comparable efficacy to that of the reference standards. Additionally, these compounds were tested for their reversibility potential and found to be reversible inhibitors of the MAO-A enzyme, as a 100-fold dilution with the substrate solution restored over 68 % enzymatic activity. The in vivo FST and TST results corroborated well with the findings from in vitro MAO inhibition. Further, antioxidant properties were assessed using in vitro assays and the compounds were computationally analyzed through molecular docking, MD simulation, and DFT studies (in silico). The molecular docking results revealed that the compounds showed stronger interactions with key amino acid residues and better docking scores than the studied standard drugs. All selected compounds demonstrated favorable ADME properties, including good blood-brain barrier penetration and gastrointestinal absorption. Molecular dynamics simulations and DFT studies also confirmed the stability of VK16 and VK19 within the MAO-A binding site. Overall, VK16 and VK19 are emerged as promising antidepressant candidates, warranting further investigation for clinical development.

Antioxidant; DFT; Depression; Docking; MAO-A; MD simulation; Mental health; Reversibility.