’One-pot’Synthesis Of Fused-heterocycles Via A Silver(Ⅰ)-catalyzed Cascade And The Discovery Of KCNQ2Channel Activator Based On Old Drugs

The dissertation contains two chapters. Chapter one regards’one-pot’synthesis of dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinlines via a silver(I)-catalyzed cascade approach. Chapter two regards the discovery of KCNQ2channel activator on the basis of old drugs.Fused-isoquinolines are widely distributed in alkaloids and biologically important synthetic substances, and exhibit a broad spectrum of biological properties. Despite some approaches to prepare fused-isoquinolines have been reported over the years, it is noteworthy that most of the described methods suffer from high cost of the catalyst, complicated synthetic steps, harsh reaction conditions or poor yields. Therefore, in chapter one, we have developed an efficient synthetic methods for the construction of potential bioactive fused polycyclic compounds through exploring new one-pot cascade strategies, namely that using readily available2-(phenylethynyl)benzaldehyde (1.Oequiv) and (2-aminophenyl)-methanol (1.2equiv) as the starting material, AgNO3(5mol%) as the catalyst, keeping at80℃for3hours gave the desired product in good yields (45-94%). We also explored the scope, electronic effect and steric hindrance effect of this methodology. In addition, we proposed a possible reaction mechanism and confirmed the structure of the targe product with a x-ray diffraction. These research in this chapter provided an useful tool for the construction of potential bioactive fused polycyclic compounds.Chapter two regards the discovery of KCNQ2channel activator on the basis of old drugs. The current drug discovery model is a costly, time-consuming and high risk project. It may be an effective strategy for the drug discovery throughidentifying new uses for the marketed drugs. So, we have screened a self-built database containing more than500old drugs via a highthroughput screen strategy, and Mancozebwas validated electrophysiologically as a KCNQ2activator with an EC50value of0.92±0.23μM. Further examination showed that manganese but not zinc ethylene bis-dithiocarbamate is the active component for the positive modulation effects. In addition, the compounds are effective when the metal ions are substituted by iron, but lack potentiation activity when the metal ions are substituted by sodium, signifying the importance of the metal ion. However, the iron (Fe3+) alone, organic ligands alone or the mixture of iron with the organic ligand did not show any potentiation effect, suggesting as the active ingredient is a specificcomplex rather than two separate additive or synergistic components. Our study provides new insight into the possible mechanism of Mancozeb toxicity in the nervous system.