Novel Propofol Analogs: Design, Synthesis and Evaluation of Dihydrobenzofuran Derivatives as General Anesthetics

<b>Background</b>: Propofol is used worldwide as a short-acting intravenous anesthetic in clinical practice; however, side effects such as injection pain and respiratory depression remain clinically relevant. Therefore, identification of safer propofol analogs is required. <b>Method</b>: In response to the urgent need for optimized potency and reduced side effects, a series of dihydrobenzofuran derivatives were designed as expectedly better propofol analogs through conformational restriction. A loss of righting reflex assay was conducted to evaluate the sedative/anesthetic properties of the synthesized compounds, and a respiratory depression test was performed for safety assessment. <b>Results</b>: Most of the designed compounds were shown to possess promising anesthetic properties as propofol analogs. The represented <b>53A</b> had higher potency and a wider safety margin (ED₅₀:3.898 vs. 8.040 mg/kg in mice; 2.985 vs. 5.894 mg/kg in rats; TI (therapeutic index): 6.172 vs. 5.061 in mice; 4.362 vs. 2.580 in rats) than propofol, and fast onset and recovery times were maintained. The phosphate prodrug <b>56A</b> also exhibited better efficiency and safety than fospropofol, along with a longer duration and faster recovery time in sedative profiles. Furthermore, alleviation of the adverse effects of respiratory depression has been demonstrated. <b>Conclusions</b>: <b>53A</b> has the potential to be selected as a preclinical candidate for clinical development.