Exploring the Potential of Quinoline-Containing Pyrazoline Derivatives as Antidepressant Agents: In Vivo and In Silico Studies.

INTRODUCTION/

Objective

Depression is a common mental disorder, affecting over 300 million people worldwide. Currently available treatments, such as SSRIs, SNRIs, TCAs, and MAOIs, have limited effectiveness and cause side effects. The pharmacological potential of compounds based on diverse novel heterocyclic scaffolds, including quinoline-appended pyrazoline analogues, has been well recognized.

Methods

Ten derivatives of 1, 3, 5-trisubstituted pyrazoline, namely BS-1 to BS-10, were synthesized from chalcone derivatives in reaction with thiosemicarbazide/semicarbazide analogues. The complexes were identified by physicochemical and spectral analyses (FT-IR, 1H-NMR, 13C-NMR), and in silico studies comprised molecular docking against MAO-A and molecular dynamics simulations. Drug-likeness and toxicity analysis was performed using SwissADME, PreADME, and Pro- ToxWeb. Antidepressant potentials were evaluated in vivo using the Forced Swim Test (FST) and Tail Suspension Test (TST) in Swiss albino mice; behavioral parameters and DPPH and H2O2 assays determined antioxidant activity.

Results

Docking studies revealed strong binding to MAO-A, with the highest scores observed for BS-7 and BS-8 (-10.8 and -11.7 kcal/mol). Stable interactions were also identified in molecular dynamics simulations, particularly for BS-7. In vitro assays (DPPH) indicated antioxidant activity, and the IC50 values of BS-7, BS-8, and BS-10 were 43.65, 66.42, and 44.11 μg/mL, respectively. Also, BS-7 BS-8, and BS-4 compounds demonstrated antioxidant activity (H2O2) with IC50 values of 9.06 ± 2.12, 11.38 ±1.00, and 12.89 ±2.25 μM, respectively. In vivo screening showed that specific compounds, such as BS-8 (30 mg/kg), significantly reduced FST and TST immobility time (p < 0.0001), whereas BS-7 produced significant effects only in TST.

Discussion

BS-8 demonstrated superior antidepressant-like activity compared to BS-7 in both FST and TST without affecting locomotor performance. In antioxidant assays, BS-7 showed moderate free-radical scavenging in the DPPH assay, whereas BS-8> BS-7 exhibited greater hydrogen peroxide (H2O2) scavenging activity, indicating complementary antioxidant profiles that may differentially contribute to their observed biological effects.

Conclusion

Quinoline-based pyrazoline analogues BS-8 > BS-7 showed antidepressant-like and antioxidant activities without affecting locomotor or muscle function, indicating their potential as lead compounds for novel antidepressant development.