Design,Synthesis And Biological Evaluation Of Fluorinated Protein Tyrosine Phosphate 1B Inhibitors

Diabetes is one of common metabolic diseases. As the main feature, blood glucose of patients is always beyond the normal range. Long-term high blood sugar would cause damage to the body’s organs and tissues, such as the eyes, kidneys, blood vessels, nervous system damage or function of the heart and chronic disorders. At present, some insulin sensitizers appear to promote the development of clinical research in the treatment of type 2 diabetes. Protein tyrosine phosphatase 1B is an emerging therapeutic target for diabetes protein. Introduction of fluorine(or fluorine-containing groups, such as trifluoromethyl) is a new approach for fast-tracking drug development and optimization of structural transformationWith the goal of higher activity fluorinated protein tyrosine phosphatase 1 B inhibitors, we designed and synthesized compounds by molecular docking instruction, and tested the in vitro activity of PTP1 B.Firstly, we designed a series of compounds based on the basic skeleton of marine natural product BPN. We performed Computer Aided Drug Design molecular docking for the screening of better structure. We use ChemBioDraw and Chemdraw 3D software to fit compound structures as molecular docking requirements. With PyMOL and MGL Tool, we prepared *.pdbqt file as AutoGrid required. Run AutoGrid determined docking area of the receptor protein and ligand molecules. Run AutoDock to perform molecular docking. According to the results of molecular docking we selected five compounds.We designed the synthesis route for the selected compounds by the result of computer simulation screening. After bromination, oxidation-reduction, Friedel-Crafts alkylation reaction to complete the target compound(3-bromo-2-(2, 3-dibromo-4, 5-dimethoxybenzyl)-4, 5-dimethoxyphenyl)methanol, 1, 2, 4-tribromo-3-(2-bromo-3-fluoro-6-methylbenzyl)-5, 6-dimethoxybenzene, 4-(4-bromo-2, 3-dimethoxy-6-methylbenzyl)-2-fluorophenol, 2-(4-bromo-2, 3-dimethyl-6-toluene)-6-fluoro-phenol, 2-bromo-3-(3, 4-difluorobenzyl)-1-fluoro-4-methylbenzene, 2-(3, 5-bis(trifluoromethyl)benzyl)-3-bromo-4-fluoro-1-methyl-benzene.Then we performed in vitro PTP1 B inhibitory activity of these compounds. The meta-fluorinated and para-fluorinated compounds showed better inhibitory activity.Through computer-aided drug design of molecular docking methods performed screening compounds to inhibit the activity of the PTP1 B. Computer-aided drug design greatly accelerated the process of drug design and development. Provides experience and research methods for further study on the fluorinated PTP1 B inhibitor.