Oxindole derivatives alleviate paracetamol-induced nephrotoxicity and hepatotoxicity: biochemical, histological, and computational expressions

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Abstract
Oxindole is a nature-derived heteroaromatic nucleus with a history of preclinical uses in various conditions. In this study, oxindole derivatives, 6-chloro-3-(3-hydroxybenzylidene) indolin-2-one (3OH) and 6-chloro-3-(4-hydroxybenzylidene) indolin-2-one (4OH) were evaluated for nephroprotective and hepatoprotective effects. Paracetamol-induced nephrotoxicity and hepatotoxicity model was used in mice. Tissue histology and serum biochemistry were carried out to further support in vivo activity. Compound 3OH reduced serum urea and creatinine levels by 51.8% and 64.6%, respectively (p < 0.0001). Excretion of creatinine by 3OH 10 mg was 52.8% as compared to silymarin. In case of urinary excretion of urea, the significant rise in excretion was observed in 4OH 15 mg (30.4%; p < 0.05) and 3OH 10 mg group (29.24%; p < 0.05). The compound 3OH exhibited restorative pattern of the renal tissues with slight inflammatory infiltrations. In case of hepatoprotective activity, 3OH reduced (59.9%; p < 0.0001) serum ALT at 5 mg even more than silymarin and all other doses of oxindole derivatives. In case of serum AST, all treatment groups produced significant (p < 0.0001) reduction except 3OH 15 mg. Computational studies supported the results as both derivatives were found to have promising interactions with enzymes at lower binding energies. Compound 3OH which possesses a hydroxyl group based on aromatic ring at meta position was the most successful drug candidate throughout this study. In a nutshell, the selected compounds elicited significant nephroprotective and hepatoprotective-like effects in mice.

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