Design, synthesis, and biological evaluation of novel isobenzofuran-1(3H)-one derivatives with antioxidant properties and improved oral bioavailability.

Bioavailability is a critical determinant factor of a drug, especially for its therapeutic efficacy, safety and commercial feasibility. Many active small molecule drugs suffer from poor oral bioavailability. 3-Butylisobenzofuran-1(3H)-one (NBP) is an approved small molecule agent by the CFDA for the treatment of acute cerebral ischemic stroke. NBP inhibits platelet aggregation, reduces brain infarct size, and attenuates ischemic-induced oxidative damage. However, the efficacy of NBP is limited due to its low bioavailability and high hydrophobicity. Sometimes, administration of high doses and increased frequency of NBP causes hepatotoxicity. Here, we designed, synthesized and evaluated a series of novel 6-substituted 3-butylisobenzofuran-1(3H)-one derivatives in vitro and in vivo and compared them with NBP or Br-NBP. Several compounds in the series showed better protective effects by preventing H2O2-induced LDH release and reduced ROS production in PC12 cells. In the in vivo pharmacokinetic study, compound 23 and compound 24 showed improved oral bioavailability and achieved F% = 52% and 44%, respectively. In addition, ADMET profiling and molecular docking simulations of 23 and 24 with MAO-A and MAO-B were conducted and the data included.