Synthesis, In Vitro Anti-Inflammatory Activity, Molecular Docking, Molecular Dynamics and DFT Calculations of Thiazoline-2-Thione Derivatives

The objective of this study was to synthesize thiazoline-2-thione derivatives (1a, 2b, 3c and 4d) and examine their anti-inflammatory properties as potential alternatives to Aspirin (NSAID), which is known for its side effects, including liver damage. The study employed a multifaceted approach that integrated in vitro assays, molecular docking, ADMET predictions, molecular dynamics simulations (300 ns for each system) and detailed DFT calculations. These four molecules were initially evaluated for their effectiveness in inhibiting the denaturation of bovine serum albumin (BSA), a key indicator of their potential anti-inflammatory activity. The results show that 4d displayed notable inhibitory potential against BSA denaturation, with an IC50 value of 21.9 µg/mL, outperforming the efficacy of Aspirin (22 µg/mL). In comparison, 3c exhibited an IC50 value of 31.7 µg/mL. Molecular docking studies with the BSA active site revealed that 4d and 3c had the highest binding affinities, with binding energies (∆G) of −5.274 and −4.731 kcal.mol−1, respectively. Aspirin showed a ∆G of −4.641 kcal.mol−1. These findings suggest that 4d and 3c molecules exhibit stronger interactions with BSA, indicating superior anti-inflammatory activity compared to Aspirin. In addition, molecular dynamics simulations, cross-dynamic correlation matrix (DCCM), free energy landscape (FEL), MM-PBSA and detailed DFT calculations provided further evidence that 4d formed stable molecular interactions with the BSA receptor. These analyses highlighted the strong binding stability of 4d, indicating that it maintains consistent interactions over time. The results also suggested that 4d exhibits favorable energy profiles, good pharmacokinetic features and optimal molecular behavior within the BSA active site. Finally, the results of this study are promising for the development of new anti-inflammatory drugs, highlighting potential compounds that could offer effective and safer alternatives to existing treatments.