Synthesis And Biological Evaluation Of Gem-Difluoromethvlenated Statin Derivatives As HMG-CoA Reductase Inhibitors

HMG-CoA reductase inhibitors-statins are widely used as lipid-lowing drugs through effectively blocking the rate-limiting step of cholesterol biosynthesis.The main content of this paper is to combine the advantages of statins over hypolipidemic and the benefits of fluorine atom during the medicinal chemistry. The structure activity relationship of statin derivates was studied by using molecular docking. And organic synthesis was using the method of a sequence of reaction, such as Reformastky reaction. Claisen ester condensation, sodium borohydride reduction, alkaline hydrolysis, DAST fluoronation, difluoro-methylene unit was introduced into the statin hydrophilic side chain,3, 5-dihydroxy pentanoic acid at the 4-position. Twenty gem-difluoromethylenated statins, lactone and dehydration statins derivatives were synthesized and characterized by 1H NMR, 13C NMR,19F NMR, IR, HRMS. The inhibition activity of the HMG-CoA reductase inhibitor analogs was detected. Through the selection of these compounds, three compounds with 3, 5-dihydroxy-4-gem-difluoro valerate structure exhibited good inhibition activity against HMG-CoA reductase.