Elaboration of newly synthesized tetrahydrobenzo[b]thiophene derivatives and exploring their antioxidant evaluation, molecular docking, and DFT studies

Herein, 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1) was synthesized in excellent yield through gewald reaction in multi components one pot reaction. Compound 1 was utilized as a building block to synthesize a new group of tetrahydro benzo[b] thiophene congeners. The chemical structure of all the novel tetrahydro benzo[b]thiophene derivatives were elucidated through the melting point, elemental analysis, FT-IR, ¹H-NMR, and mass spectroscopy. Furthermore, the total antioxidant capacity (TAC) of all the newly synthesized heterocyclic derivatives was evaluated according to the phosphomolybdenum method using ascorbic acid as standard. The findings revealed that compounds 1, 16, and 17 demonstrated significant antioxidant potency comparable to that of ascorbic acid. This suggests the potential of these heterocycles as promising candidates for antioxidant drugs in the treatment of oxidative stress-related diseases. Finally, molecular docking was conducted to study the binding affinity for the most potent antioxidant compounds 1, 16, 17 and ascorbic acid inside the interactions of compounds 1, 16, and 17 with the Keap1 (Kelch-like ECH-associated protein 1) protein (PDB: 7C5E), compared to the co-crystallized ligand triethylene glycol (PGE) and ascorbic acid as a reference drug for antioxidants. DFT calculations and global descriptors were calculated for the most potent compounds to correlate the relation between chemical structure and reactivity.