| HMG-CoA reductase inhibitors(statins)can effectively block the synthesis of cholesterol in the human body,so they are widely used as lipid-lowering drugs.But statins can only inhibit HMGR and cannot deal with complex pathological systems.For example,the effect of regulating the level of triglycerides in blood lipids is not obvious.In clinical practice,statins are often used in combination with drugs such as niacin and ligustrazine to assist statins in the treatment of hyperlipidemia.Based on clinical dates,this paper designed a series of statin-nicotinic acid and statin-ligustrazine conjugate drugs by the principles of conjugated drugs.This work used the molecular docking module in computer-aided drug design to score the designed candidate small molecule compounds,the scoring results show that the designed candidate small molecule compounds can effectively bind to the HMGR protein.Based on this,the selected statin fragments were determined to be four statin drugs including atorvastatin,rosuvastatin,pravastatin and pitavastatin.Through oxidation reaction,bromination reaction,esterification reaction and other organic synthesis methods,the pharmacophore of statin(3,5-dihydroxyvaleric acid)is combined with niacin and ligustrazine through linkers without linkers and linkers of different lengths.After coupling,32 candidate compounds were synthesized,and their structures were confirmed by 1H NMR,13 C NMR,HRMS,etc.In vitro HMGR inhibitory activity of 32 synthesized target compounds was determined,although the activity was not higher than positive in the end.But this work still has certain reference significance for the development of this type of hypolipidemic conjugated drugs. |
