OBJECTIVE To design and synthesize a series of novel thioether-bridged N-acetylcysteine derivatives and evaluate their protective effects against drug-induced liver injury.

METHODS Starting from L-cysteine, the target compounds were prepared through steps including mercapto group benzylation, amino group Boc protection, and amino condensation. An acetaminophen-induced LO2 hepatocyte injury model was used for in vitro activity screening, and the compounds with superior activity were selected for in vivo pharmacodynamic studies in mice and pharmacokinetic studies in rats.

RESULTS Eight target compounds(6a−6h) were successfully synthesized, and their structures were confirmed by ¹H-NMR, ¹³C-NMR and high-resolution mass spectrometry. In vitro experiments showed that compounds 6b, 6c, and 6e significantly increased the proliferation rate of injured hepatocytes. Among them, compound 6c restored the cell proliferation rate to (112.3±6.8)% and effectively reduced malondialdehyde content. Pharmacodynamic experiments in mice showed that in acetaminophen-induced acute liver injury model in mice, compound 6c significantly reduced serum alanine aminotransferase, aspartate aminotransferase, and glutamate dehydrogenase levels 24 h after administration, with effects comparable to the positive control N-acetylcysteine. Pharmacokinetic studies in rats showed that compound 6c had an oral half-life of (5.62±0.73)h and an oral bioavailability of 52.8% in SD rats, which was significantly higher than that of N-acetylcysteine.

CONCLUSION Compound 6c exhibits significant hepatoprotective activity both in vitro and in vivo, along with excellent pharmacokinetic properties, making it a valuable lead compound for further research.