New acetamide-sulfonamide scaffolds with potential renal radiomodulatory effects: Insights into NF-κB pathway interactions.

With the increased use of radiation in cancer therapy, new effective antioxidants and anti-inflammatory agents are required to alleviate the negative impact caused by irradiation. A set of novel N-substituted-2-((2-oxo-2-((4-sulfamoylphenyl)amino)ethyl)thio) acetamide derivatives 3-14 was synthesized to act as possible radiation mitigators. The synthesized compounds were screened for their anti-inflammatory and antioxidant potential using selective COX-2 inhibitory activity and DPPH assays compared to celecoxib and ascorbic acid, respectively. Compound 9 was the most active in this series with selective COX-2 inhibitory activity (IC50 = 0.373 μM), and free radical scavenging properties (IC50 = 4.89 μM). In vitro and in vivo studies demonstrated that compound 9 exhibited a high safety profile, with low cytotoxicity on normal cells (IC50 > 800 μM) and a median lethal dose (LD50) of 300 mg/kg. The potential renal radiomodulatory effect of the promising candidate was investigated in mice exposed to gamma radiation (6 Gy). Compound 9 successfully reduced radiation-induced oxidative stress, as seen by lower levels of reactive oxygen species (ROS), malondialdehyde (MDA), and enhancement in the levels of reduced Glutathione (GSH) in kidney tissues. Moreover, compound 9 reduced kidney inflammatory markers; Nuclear factor kappa B (NF-κB) and Interleukin 6 (IL-6) in irradiated mice, while lowering serum urea and creatinine levels relative to untreated irradiated group. Compound 9 additionally modified the histological alterations caused by gamma irradiation-induced tubular epithelial cell necrosis. Accordingly, compound 9 can help to reduce the adverse effects of irradiation.