Design, Synthesis, Characterization, ADME Profiling, and Protective Role of Bis-Chalcones against Chlorpyrifos-induced Hepatorenal Damage in Male Albino Rats

Background: Pesticides, particularly organophosphates (OPs) such as chlorpyrifos, pose major public health risks through environmental contamination, dietary residues, and occupational exposure, with metabolites widely detected in human biomonitoring. Chlorpyrifos induces hepatorenal toxicity primarily through hepatic cytochrome P450-mediated bioactivation to chlorpyrifos-oxon, leading to reactive oxygen species overproduction, oxidative stress, and organ injury.Objectives: To evaluate the protective potential of synthesized bis-chalcone derivatives against chlorpyrifos-induced oxidative stress and hepatorenal damage in male albino rats.Materials and methods: Three bis-chalcone derivatives (A1-A3) were synthesized by environmentally friendly Claisen-Schmidt condensation, characterized by proton nuclear magnetic resonance and Fourier-transform infrared spectroscopy, and assessed for purity by elemental microanalysis (CHNO). Oxidative stress, liver, renal, and lipid biomarkers were measured in 56 male albino rats assigned to eight groups (7 rats for each group), comprising one control group, three groups receiving bis-chalcones (A1-A3) alone, one chlorpyrifos group, and three groups pretreated with A1, A2, or A3 followed by chlorpyrifos (oral gavage, 14 days).Results: Chlorpyrifos markedly increased thiobarbituric acid reactive substances (TBARS), liver enzymes, total bilirubin, urea, total cholesterol, and triglycerides, while decreasing reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), total protein (TP), and albumin (ALB). A1 pretreatment most effectively normalized these indices (e.g., TBARS 28.76 ± 2.18 nmol/L, GSH 14.92 ± 0.56 µmol/L, aspartate aminotransferase (AST) 78.4 ± 4.1 U/L, and alanine aminotransferase (ALT) 58.7 ± 3.2 U/L; all P-values < 0.05 vs. chlorpyrifos).Conclusion: Bis-chalcone derivatives, particularly A1, exert strong protective effects against OPs toxicity in rats by restoring oxidative balance and preserving hepatocellular, renal, and metabolic functions.