Design, Synthesis And Activity Study Of3-(2-Cinnamamidopropanoyl)Thiazolidine-4-carboxylic Acids As Novel Angiotensin Converting Enzyme Inhibitors (ACEIs)

Hypertension has become “the number one killer” now, which threaten to the human health.Angiotensin-converting enzyme （ACE） is a kind of dipeptidase, which contains zinc ions. In the vivo, itmainly converting angiotensin I to angiotensin II, making bradykinin inactivation, causing vasoconstriction,leading to high blood pressure of the body. So angiotensin-converting enzyme plays a very important rolein the rennin-angiotensin system. Pharmacology studies have obvious showed that through inhibit theactivity of ACE can significantly improve the treatment for high blood pressure disease. However, thecurrent listed ACE inhibitors, most of them have some side effects. Therefore, it is stilled needed to searchand develop novel ACE inhibotors with higer effective together with lower side effects and higherbioavailability that it is a vital significance for the study of cardiovascular disease.On the basis of the compound C-5, whch have been demonstrated that it has better ACE inhibitionration, to reconstruct its configuration, using the thiazolidine-4-carboxylic acids to replace the proline withthe higer electrostatic potential and dendity. Meanwhile, using various substiuent cinnamic acid, designedand synthesized eighting ACEIs. The structures were verified by1H NMR,13C NMR, IR and MS.Moreover, the nine compounds were tested the inhibitory activity by the method of reversing phase highperformance liquid chromatography. The result shows that:（1） The timonacic compounds IC₅₀values werebetter than proline, acheived the expected goals.（2）In the tested compounds, the compounnd B-8d showedthe best inhibitory activity, the IC₅₀value is50μM.On the other hand, in order to synthesize this class of ACE inhibitors in a more efficient andenvironment-begin way, one method for bond formation have been developed in this dissertation. A simpleand efficient method of copper （II） complex as a catalyst for N-arylation of imidazoles was established.Under the conditions, the aryl iodides, bromides and chlorides all can be bonded with imidazoles and gavethe better yields. The method has the advantages of mild conditions, easy to operate, the catalystspreparation is simple and stability. But when the method was applied to synthesize the intermediates ofACE inhibitors. Unfortunately, it did not get the expecting target product, it may be due to the chaincarboxyl of benzene ring side has strong electron-withdrawing effect, bring to reduce the electron clouddensity of benzene ring, it is not easy to achieve coupling reaction.