Design, Synthesis, Computational Analysis, and Pharmacokinetic Evaluation of Pyrazole–Thiazole Hybrids as Potential Antiinflammatory Agents

ABSTRACT A series of ( E )‐4‐(aryl)‐2‐(2‐((1,3‐diphenyl‐1 H ‐pyrazol‐4‐yl)methylene)hydrazineyl)thiazoles ( 4a – 4d ) were synthesized via the condensation of 1,3‐diphenyl‐1 H ‐pyrazole‐4‐carbaldehyde, thiosemicarbazide, and phenacyl bromide derivatives in ethanol using acetic acid as a catalyst, affording high yields (>80%). Structural characterization was confirmed through FT IR and 1 H NMR analyses. The antiinflammatory activity evaluated by egg albumin denaturation assay demonstrated a dose‐dependent inhibition trend. Compound 4d exhibited the highest inhibition (32.6 ± 1.91% at 100 µg/mL) compared to 4c (12.7 ± 0.25%), 4b (7.37 ± 0.49%), and 4a (7.14 ± 1.03%) in comparison with the standard drug (44.76 ± 1.08%). Molecular docking against COX‐2 revealed strong binding affinities, with docking scores ranging from –10.9 to –11.5 kcal/mol. Compound 4a showed the strongest binding through hydrophobic and π–π stacking interactions. Absorption, distribution, metabolism, and excretion (ADME) predictions suggested favorable pharmacokinetic profiles, with all compounds. DFT analysis revealed HOMO–LUMO energy gaps ranging from 3.903 to 3.989 eV, confirming chemical stability and reactivity. MESP plots revealed electrophilic and nucleophilic contacts in the synthesized compounds.