Synthesis of acyl hydrazide derivatives of α-naphthalene acetic acid as COX-2 inhibitors: in vitro evaluation, molecular docking and DFT studies

Cyclooxygenase-2 (COX-2) is a key enzyme in pain perception and inflammatory cascade that make it an attractive target to develop safer anti-inflammatory agents. In pursuit of potential anti-inflammatory agents, a new series based on α-naphthalene acetic acid has been synthesized through multi step reactions process. 1H-NMR and 13C-NMR spectroscopic techniques were used to confirm the structures of these derivatives. These compounds have been assessed for their in vitro COX-2 inhibitory activity, among them, compounds (4, 5, 13, and 3) exhibited excellent activity with IC50 value ranging from (IC50 = 0.36 ± 0.22 µM) to (IC50 = 0.43 ± 0.60 µM), while compounds (12, 11, and 14) showed significant activity. The molecular docking and density functional theory (DFT) analyses exposed that hydrazide derivatives based on α-naphthylene acetic acid displayed strong binding affinity for COX-2. Compound 13 revealed the highest binding energy of −9.771 kJ mol−1 and the lowest IC50 (0.43 µM) over π-π interactions and multiple hydrogen bonds. DFT study exposed that compound 13 influenced the highest softening and the smallest HOMO-LUMO energy gap, representing improved reactivity. In general, the computational as well as experimental consequences specify that compound 13 is a potent COX-2 inhibitor.