The Synthesis And Activity Study Of Phthalides And α-lipoic Acid Derivatives

Orlistat irreversibly inhibits gastrointestinal pancreatic lipase, which results in restraining lipid absorption and weight loss. Orlistat is by far the best diet pills on the market, but its side effects are also obvious. So the design novel low toxic and more potent inhibitors of gastrointestinal pancreatic lipase has become an important research field for searching antiobesity drugs.Phthalides have a variety of biological activities, especially n-Butylphthalide (NBP), which can improve brain microcirculation, and have the effect of the treatment of cerebral ischemia.Based computer aided drug design to simulate the co-crystal structure of pancreatic lipase and orlistat,11 phthalide derivatives were designed by Docking method. All new compounds were characterized by 1H-NMR,13C-NMR, HRMS. Inhibiting activities on pancreatic lipase of synthesized compounds were tested, and compound 2,5,7 shows 49%,30%,35% inhibition rate on pancreatic lipase at the concentration of 1 mg/ml.New Delhi-metal beta lactamase (NDM-1) belongs to class B metallo-β-lactamase (MBLs) which has 2 zinc ions and 1 water molecule as the active catalytic center, thus blocking 2 zinc ion can inhibit the function of NDM-1. It was found that mercapto compounds may bind to Zn2+ through coordination bond, which may be potential NDM-1 inhibitors.Alpha lipoic acid (ALA) is a potent antioxidant, which possesses a variety of biological activities. For example, it can eliminate free radicals, remove human keratinocyte, bind with metal ions and treat radiation damage.Based on sulfur-containing compounds that bind to Zn2+ of enzymes,10 α-lipoic acid derivatives were designed and synthesized. All new compounds were characterized by 1H-NMR,13C-NMR, HRMS. Compound 20 shows potent inhibition on NDM-1 with the IC50 of 12μM more than Captopril (the IC50 of 16μM).