Studies On Synthesis And Bioactivity Of The Novel Derivatives Of Arecoline

Atherosclcrosis (AS) is the most frequent disease harmful for the health and livesof the elderly and can lead to cerebrovascular, coronary heart disease. Thepathogcnesis of athcrosclerosis is complex, and available Anti-atherosclerosis drugsstill can not meet the clinically requirements.There is target for acetylcholine on Vascular endothelial cells, called endothelialtarget for acetylcholine (ETA). The function of ETA is normal or not, which is closelyrelated to cardiovascular diseases including atherosclerosis. ETA antagonist is moreharmful for smooth muscle cells of atherosclerosis lesions induced by high cholesterol;but the ETA agonist has clear role of controling high cholesterol-inducedatherosclerosis. The natural arccoline is ETA agonist. It can control atherosclerosis byexciting ETA to increase NO release of vascular endothelial cells; it can inhibit theadhesion of early AS mononucleosis and delay the development of AS by excitingETA to inhibit the overexpression of adhesion molecule ICAM-1 and the chcmokineIL-8 and MCP-1. So, it has broad application prospects to use ETA agonist arccolinc asthe leading compound to control athcrosclerosis. In this paper a series of novelderivatives of arecoline was designed and synthesized with the arecoline as leadcompound and the basic theories of drug design, such as bioisosterism andcombination of activity. We expect to found novel compounds which can excite ETA,relax arteries and be useful to control AS.Part One: Target Compounds DesignIn this paper 60 new compounds and 22 target compounds of 5 types have beendesigned and synthesized with the arecoline as lead compound and the basic theoriesof drug design, such as bioisosterism and combination of activity.The clinical effect of arecoline is poor because the ester group of arecoline is easyhydrolysised and instability metabolism of the ester moiety. So, to improve its stabilitywas one part work of structure modification of arecoline. It is the most widely used andeffective method to use bioactive five-membered heterocyclic as bioisosteres of theester group of arecoline. Using substituted thio-1,3,4-thiadiazole and substituted thio-1,2,4-triazole as bioisosteres of the ester group of arecoline, the arecolinederivatives (â…¡,â…£) containing substituted thio-1,3,4-thiadiazole ring and the arecolinederivatives (â… ,â…¢,â…¤) containing substituted thio-1,2,4-triazole ring were designed.Part Two: Target Compounds SynthesisIn this paper a series of novel arecoline analogues containing substitutedthio-1,3,4-thiadiazole ring and substituted thio-1,2,4-triazole ring was synthesized bychemical methods, their structure were determinated by elemental analysis, ¹H NMR,IR and MS.2. 1 Synthesis of the target compoundsâ…¡andâ…£2-pyridin-3-yl-5-mercapto-1,3,4-thiadiazole dissolved in methol and water wastreated with sodium hydroxide, then with RX to give the corresponding intermediates.The intermediates reacted with iodomethane in acetone to give the correspondingpyridinium iodides, then were reduced with sodium borohydride in aceticacid-alcohol to give the target compounds (â…¡andâ…£).2.2 Synthesis of the target compoundsâ…¢andâ…¤2-pyridin-3-yl-4-amino-5-mercapto-1,2,4-triazole was treated with the samemethod descrimed above to give the pyridinium iodides, then were reduced withsodium borohydride in methanol-water to give the target compounds (â…¢andâ…¤).2.3 Synthesis of the target compoundsâ… 2-pyridin-3-yl-4-amino-5-mercaptp-1,2,4-triazole dissolved in methol and waterwas treated with sodium hydroxide ,then with iodomethane to give the correspondingintermediates. The corresponding intermediates reacted with substituted benzaldehydecatalyzed by concentrated H₂SO₄ in alcohol, then were quaternaryed and reduced withthe same methods asâ…¢to give the target compoundsâ… .Part Three: Studies on Bioactivity of Target CompoundsThe effects of 22 target compounds on vasodilation activity were preliminarilytested in the isolated preparation of rabbit thoratic arota. The preliminarypharmacological results showed that the all candidates have varying degrees of vasodilatation activities. The compoundsâ…¡and Vof five series of target compoundshave notable vasodilatation activities, but the compounds I have relatively poorvasodilatation activities. The vasodilatation activities of 15 target compounds weresuperior to that of arecolinc. In particular, the compoundsâ… ₄,â…¡₁,â…¡₄,â…¢₃,â…¢₄,â…¤₁andâ…¤₂ were greatly superior to arecoline, their relaxing ratio were higher than 50%.Part Four: Structure-Activity Relationship Qualitative AnalysisWe could draw several conclusions by analyzing the preliminary bioactivity dataand the structure of the target compounds:â‘ The vasodilatation activities of thebiheterocyclic thio-triazole compoundsâ…¢and simple alkylthio-triazole compoundsâ…¤with active amino were superior to that of the compoundsâ… without active amino, andthe vasodilatation activities of the target compoundsâ…¢₃,â…¢₄,â…¢₅,â…¤₁,â…¤₂ weresuperior to that of arecline. These showed the amino of 1,2,4-triazole ring played animportant role in vasodilatation.â‘¡The derivatives of arecoline containing1,3,4-thiadiazole had all good vasodilatation activities. The target compoundâ…¡₁containing methylthio-1,3,4-thiadiazole ring and the compoundsâ…¡₃,â…¡₄,â…¡₅containing hydrophobic alkylthio-1,3,4-thiadiazole had significant vasodilatationactivities, but the compoundsâ…£had similar degree of vasodilatation activitiescompared arecoline.