Exploration of naphthalenone-thiazole hybrids for TNF-α, COX-2 inhibition and anti-oxidant capability

In this study, tetrahydronaphthalene carbothioamides 2, characterized by spectroscopic methods and X-ray diffraction studies, were used to develop a series of novel tetrahydronaphthalenone-coupled thiazole derivatives 3. The synthesized thiazole hybrids were evaluated for in-vitro anti-inflammatory activity against lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophage cells. Notably, compound 3f demonstrated the most potent anti-inflammatory effect by significantly reducing the expression of pro-inflammatory mediators, including nitric oxide species (IC₅₀ = 62.93 µM) and tumor necrosis factor-α (TNF-α) (67.50 µM). Additionally, 3f inhibited cyclooxygenase-2 (COX-2) (IC₅₀ = 73.18 µM compared to celecoxib 41.21 µM) expression in a dose-dependent manner. The antioxidant activity of newly generated derivatives was also assessed using the DPPH assay, with compounds 3a, 3b, and 3c showing the highest inhibition rates of 69.94%, 68.82%, and 64.77% at 100 µg/mL, respectively. Molecular docking studies targeting the active site of Human Peroxiredoxin 5 (PDB ID: 1HD2) and COX-2 (PDB ID: 4M11) were conducted to explore the potential interactions of these compounds with the receptor. Molecular dynamics (MD) simulation predicted the stability of the protein–ligand complex.