Preliminary Study On The Design, Synthesis And Antihypertensive Activity Of Niacin And Ferulic Acid Ester Twin Drugs

Hypertension is a chronic medical condition,can cause diverse complications,that may not only markedly impair the quality of life but also cause a heavy financial burden on families and the society.Currently,the incidence of hypertension is the highest in the world among all diseases,affecting one-third of the global adult population.As an important public-health challenge worldwide,the prevention,detection,treatment,and control of hypertension should receive high priority.A majority of hypertensive patients receive two or more antihypertensive drugs,and it shows that although many patients reach blood pressure goal,combination antihypertensive therapy is often needed.A drug with a single target cannot meet the demands of complex diseases and thus lack efficacy,although considerable progress has been made in the field of antihypertensive drugs.In fact,adverse events with monotherapy and combination therapy were as anticipated for the specific classes of antihypertensive therapy.Thus,the enthusiasm still remains about the development and development of safer antihypertensive.Western medicine show rapid and remarkable effects against hypertension,but these drugs show toxic effects clinically.Although Traditional Chinese medicine(TCM)has gained much attention clinically for its advantages of lower toxicity and fewer side effects,protection of target organs,multiple targets,and multiple pathways,its disadvantage is that these drugs require a long time to exert their effects.There are potential advantages in giving such agents with complementary pharmacological activities in the form of a single chemical entity.Epidemiological studies have shown an inverse association of flavonoid-rich diet consumption with the risk of hypertension and cardiovascular disease.Quercetin is the most common flavone in the human diet,it has a wide range of reported biological effects,including antioxidant,antihypertensive,antimicrobial,and antiprotozoal activities,but it has a low bioavailability.Nicotinic acid(VB3)-density lipoprotein-cholesterol and triglycerides and to markedly increase high-density lipoprotein-cholesterol(HDL-C)levels.However,because of nicotinic acid's acute vasodilatory effects,it also reduce blood pressure(BP),which is an cardiovascular disease risk factor,but it has significant side effects.Ferulic acid has a better antihypertensive activity,which can against vasoconstriction and reduce spasticity of vascular endothelial cells,and have no significant side effects,while it has a shorter half-life time and low bioavailability.Therefore,combined with the structure modification,twin drug of quercetin and nicotinic acid?twin drug of ferulic acid and nicotinic acid?twin drug of ferulic acid and ferulic acid?twin drug of nicotinic acid and nicotinic acid were synthesized.In the present study,quercetin was selected to conjugate with nicotinic acid to obtain quercetin-antihypertensive twin drug.Although,linking of quercetin with VB3 in 1:1 ratio is difficult due to the presence of a number of hydroxyl groups,we have been able to conjugate this agent in the form of its derivative,quercetin tetramethyl ether(QTME)with VB3.In this paper,a novel twin drug(A)consisting of nicotinic acid(VB3)and quercetin tetramethyl ether(QTME)has been synthesized as an antihypertensive through methylation,hydrolysis,acylation and esterification starting from rutin with total yield of 79.2%.The structures of synthesized compounds were elucidated by 1H NMR,13C NMR.An efficient and convenient synthesis of four twin drugs of ferulic acid and nicotinic acid(B?C?D?E)have been achieved by a three-step reaction starting from the readily available ferulic acid and nicotinic acid in good yields is presented.Moreover,with two molecules of ferulic acid as raw materials,two ferulic acid esters(G?I)were synthesized by a one-step reaction in good yields.With two molecules of nicotinic acid as raw materials,two nicotinic acid esters(F?H)were synthesized by a one-step reaction in good yields.Pharmacological aspects,first of all,predicting antihypertension activities of the target products with the help of AT1 three-dimensional pharmacophore model,and the result shows that AT1 receptor antagonist activity following the order:compound A>compound B-E>compound G and I>compound F and H.Fit value of the target compound A is 0.934,means the good match between the pharmacophore model and the compound;predict active value is 0.0381nM,means the good antihypertensive activity.On this basis,pharmacological experiment section selected the compound A.The anti-hypertensive effects of an oral daily dose(15mg/kg)of the synthesized compounds in spontaneously hypertensive(SHR)rats and normotensive Wistar Kyoto(WKY)rats were analysed.The data demonstrate that the twin drug VB3-QTME both reduces the elevated blood pressure(P<0.001)and prolongs the action time in SHR rats(48h,P<0.001)without effect on WKY rats(P>0.05).The antihypertensive effect following the order:group I>group II>group IV.The time of duration following the order:group I>group II.Studies show that the twin drug can increase efficacy through synergy,increase fat soluble,also overcome the disadvantage quercetin of short half-life and low bioavailability.And the antihypertensive effect maintain more durable,greatly reduced side effects of niacin.However,definitive evidence of a precise mechanism of action by which VB3-QTME might decrease blood pressure remains elusive.In conclusion,nine twin drugs synthesized in the topic,the preparation process of QTME was optimized by single factor test and orthogonal test,and studies show that the twin drug can increase efficacy through synergy,increase fat soluble,also overcome the disadvantage quercetin of short half-life and low bioavailability.The study could provide certain reference to the synthesis of new antihypertensive twin drug.