Design, Synthesis And Activity Study Of Novel 1,8-naphthyridine-3-carboxamide ASBT Inhibitors

Cardiovascular disease(CVD)is the leading cause of death worldwide,atherosclerosis(AS)is the main pathological basis of CVD.Hypercholesterolemia is dominated by many pathogenic factors in atherosclerosis.Therefore,it is very important to control total cholesterol content for the prevention and treatment of cardiovascular diseases.The apical sodium-dependent transporter(ASBT)protein plays an important physiological role in the enterohepatic circulation of Bile acids(BAs)and therefore essential for the BA homeostasis.Inhibition of ASBT activity facilitates the excretion of bile acids,resulting in the decrease in the total amount of BAs pool and the increase of hepatocytes through cholesterol metabolism to synthesize BAs and reducing the total cholesterol content.Therefore,inhibition of ASBT activity is a potential strategy for cholesterol lowering drugs.In this paper,we will find a new high efficiency and low toxicity ASBT inhibitor through the combination of C ADD virtual screening and chemical synthesis.It is divided into two parts:1.Homologous modeling and Docking study of ASBTIn this paper,combined with the idea of CADD,3zuy is used as template sequence by homologous modeling method and ASBT preliminary model M0006 is established using Discovery Studio 3.1.The model is further optimized by molecular dynamics simulation experiment.Finally,the conformation stable receptor structure model M0006Y is obtained.The evaluation of the 3D structure of the model shows that the model is reasonable and reliable in three-dimensional structure and energy.Then we use the M0006Y 3D model as the receptor with the ASBT inhibitors that have been reported to S-1647,R-146224 and the preliminary synthesis of 1,8-naphthidine compounds in this group.Most of the docking results are from-7.000 to-10.000,receptor and ligand molecules have strong binding ability,and the docking results are ideal.From the docking effect of the receptor M0006Y with the ligand,we found that the amino acid residues of the ligand small molecules and the possible binding sites of the protein receptor are mainly Asn10,Thr110 and Tyr117.These amino acid residues can form hydrogen bond interaction with the ligand and produce electrostatic interaction.The small ligand molecules are mainly in the hydrophobic pockets of M0006Y through extensive Van der Waals' force and hydrophobic interactions.The terminal quaternary ammonium salts in the compound structure are located outside of the cavity and conform to the general hydrophilic environment.2.Design,synthesis and activity study of 1,8-naphthalidine-3-formamide ASBT inhibitorsOn the basis of the prophase 1,8-naphthidine-3-methamides,in order to systematically study the effect of position and types of the 1 and 3 substituent on the water solubility and inhibitory activity of ASBT,A and B compounds were designed,and 66 target compounds were synthesized through 8 steps reaction and their initial ASBT inhibitory activities were determined.The results showed that the 18 target compounds with inhibitory activity greater than the positive control S-1647,and the 6 target compounds(CI-2-6,CI-2-7,CI-3-8,F-1-1,F-1-3 and F-1-4)with the inhibition rate of more than 60%in 50?M.The 6 compounds are docked with the M0006Y and the results showed that the binding mode of the receptor and ligands was consistent with the previous docking results,which was consistent with expectations,and the compounds were better docking,which suggested that it might have a better ASBT inhibition activity.B series compounds are introduced into the double quaternary ammonium salt chain in 1 and 3 sites of 1,8-naphthalene.This research work is still in progress,and the results are worth looking forward to.Through the above research work,128 compounds were synthesized in this paper,including 66 target compounds,and most of the target compounds were confirmed by1H NMR,13C NMR and HRMS.