Identification of novel diclofenac acid and naproxen bearing hydrazones as 15-LOX inhibitors: Design,synthesis, in vitro evaluation,cytotoxicity, and in silico studies

Inflammation is the immune system's adaptive response to tissue dysfunction or homeostatic imbalance, inducing fever, pain, physiological and biochemical changes via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. NSAIDs (non-steroidal anti-inflammatory drugs), such as diclofenac acid and naproxen, are the most common inhibitors of the COX pathway. These drugs, however, are currently being studied as LOX inhibitors as well. Therefore, in the present study, a novel series of diclofenac acid and naproxen-bearing hydrazones 7(a-r) were designed, synthesized, and characterized by different spectroscopic methods like ¹H NMR, ¹³C NMR, IR and HRMS (EI) analysis. All these synthesized compounds were evaluated for their in vitro inhibitory potential against the Soybean 15-lipoxygenase (15-LOX) enzyme. These compounds exhibited varying degrees of inhibitory potential ranging from IC₅₀ 4.61 ± 3.21 μM to 193.62 ± 4.68 μM in comparison to standard inhibitors quercetin (IC₅₀ 4.84 ± 6.43 μM) and baicalein (IC₅₀ 22.46 ± 1.32 μM). The most potent compounds in the series were compounds 7c (IC₅₀ 4.61 ± 3.21 μM), and 7f (IC₅₀ 6.64 ± 4.31 μM). These compounds were found least cytotoxic and showed 96.42 ± 1.3 % and 94.87 ± 1.6 % viability to cells at 0.25 mM concentration respectively. ADME and in silico studies supported the drug-likeness and binding studies of the molecules with the target enzyme.