Phenolic acid-tethered isoniazid for abrogation of drug-induced hepatotoxicity: design, synthesis, kinetics and pharmacological evaluation.

Morphological and metabolic aberrations in the liver caused by long-term use of anti-tubercular agent isoniazid (INH) have been an issue of great concern in tuberculosis treatment. To resolve this issue, a novel hepatoprotective prodrug strategy was developed by combining the antioxidant property of phenolic acids with INH moiety for probable synergistic effect. In this work, INH was conjugated with phenolic antioxidants using Schotten-Baumann reaction through biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis and in vitro release studies were carried out using HPLC. They were found to be stable in acidic (pH 1.2), basic (pH 7.4) buffers, stomach homogenates of rat whereas hydrolyzed significantly (56.03-88.62%) in intestinal homogenates over a period of 6 h. Further their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, oxidative stress markers, and histopathology studies. All the prodrugs were effective in abating oxidative stress and re-establishing normal hepatic physiology. Especially the effect of prodrugs of INH with gallic acid and syringic acid in restoring levels of enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy. The findings of this investigation demonstrated that reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.