Design, Synthesis and Preliminary Bioactivity Evaluation of N‐acetylcysteine Derivatives as Antioxidative and Anti‐inflammatory Agents

Abstract N‐acetylcysteine (NAC) is a commonly used mucolytic agent and antidote for acetaminophen overdose. For pulmonary diseases, NAC exhibits antioxidative properties, regulates cytokine production, reduces apoptosis of lung epithelial cells, and facilitates the resolution of inflammation. However, the efficacy of NAC in clinical trials targeting different pathological conditions is constrained by its short half‐life and low bioavailability. In the present study, a series of NAC derivatives were designed and synthesized to further enhance its pharmacological activity. Structure‐activity relationship (SAR) studies were conducted to optimize the activating groups. In vitro evaluations revealed that compounds 4 r , 4 t , 4 w , and 4 x exhibited superior antioxidative and anti‐inflammatory activities compared to the positive controls of NAC and fudosteine. The ADME prediction analysis indicated that these compounds exhibited a favorable pharmacological profile. In‐vivo experiments with compound 4 r demonstrated that the high‐dose group (80 mg/kg) exhibited improved therapeutic effects in reversing the HPY level in mice with pulmonary fibrosis compared to the NAC group (500 mg/kg), further proving its superior oral bioavailability and therapeutic effect compared to NAC.