Design and development of pyrazole–thiazole hybrid derivatives as anti-inflammatory and anti-oxidant agents

• Design and development of novel pyrazole–thiazole hybrids as selective COX inhibitors. • Performed SAR-guided molecular docking of NCEs to identify potent candidates. • Accomplishment of chemical synthesis and structural characterization using FT-IR, NMR and HRMS. • Lead compound E 3 demonstrated superior COX-2 binding affinity with favorable ADMET and safety profile in silico. • In-vitro and in-vivo evaluation confirmed significant anti-inflammatory activity and improved gastric safety. Inflammation is a protective biological response triggered by infections, injuries, or irritants, but its persistent activation can lead to chronic inflammatory disorders. Cyclooxygenase (COX) plays a central role in the synthesis of pro-inflammatory prostaglandins and represents a key target for developing safer anti-inflammatory agents. In this study, novel pyrazole–thiazole hybrid compounds were designed and synthesized as potential COX inhibitors. Molecular docking studies with the COX crystal structure revealed stronger binding affinities and more favorable interactions with key residues (Tyr266, Phe295, and Leu296) compared to Celecoxib. ADME and toxicity predictions indicated good oral bioavailability, drug-like properties, and safety profiles, with compounds showing no mutagenic or carcinogenic risks. Five top-ranked derivatives (E 1 –E 5 ) were synthesized and their structures confirmed through spectroscopic analysis. In vitro evaluation revealed that compound E3 exhibited the highest anti-inflammatory activity, showing 97% inhibition. Consistently, in vivo studies using the carrageenan-induced paw edema model in Wistar rats demonstrated significant anti-inflammatory effects for all compounds, with E3 showing the highest inhibition (43.15%), comparable to the standard drug Celecoxib (42.59%). Ulcer assessments also showed better gastric safety. The hybrids also exhibited notable antioxidant activity in the DPPH assay, supporting their anti-inflammatory potential. Overall, these findings identify Compound E3 pyrazole–thiazole hybrid was identified as promising leads for the development of effective and gastro-safe multimodal therapeutics.