Design, Synthesis And Biological Characterization Of Angiotensin Converting Enzyme Inhibitors (ACEI) Drug Molecules

The development of new angiotensin converting enzyme inhibitors (ACEI) has always been a hot research topic in the field of antihypertensive drugs. Based on the "JunChenZuoShi" compounds strategy and research strategies of "Combination of Traditional Chinese Medicine (TCM) chemistry", this paper makes "Jun", "Chen", "Zuo" and "Shi" molecules connect in a certain way to form a series of novel ACEI analogues.L-Proline is the core structure of a series of ACEI drug molecular. Salvia miltiorrhiza is widely used to fight hypertension, Danshensu (DSS) is one of Salvia miltiorrhiza’s main constituents and plays an important role in antihypertensive drugs. D-Borneol has resuscitation and can promote the drug into brain, Inthispaper, proline is designed to act as "Jun" molecule, DSS as "Chen" molecule, alanineas "Zuo" molecule and borneol or N-methylpiperazineas "Shi" molecules. These groups were connected by covalent bond to form a series of new moleculars which were evaluated in vitro and in vivo to conform their activity of inhibiting ACE. The paper was divided into four chapters:(1) Introduction:The antihypertensive drugs including western medicine, Traditional Chinese medicine and Chinese-western medicine were summarized and the research strategy of "Combination of traditional Chinese medicine chemistry" was introduced.(2) The second chapter was the determination of ACEI analogues design idea. The design idea was based on the "JunChenZuoShi" drug design strategy and research strategies of "Combination of traditional Chinese medicine chemistry".(3) A series of target compounds were designed and synthesized, which included Water-soluble" Jun-Chen-Zuo-Shi" compoound (DSS-Ala-Pro-N-methyl piperazine), fat-soluble "Jun-Chen-Zuo-Shi" compound(DSS-Ala-Pro-Borneol), "Jun-Chen-Zuo" compound (DSS-Ala-Pro), "Jun-Chen-Shi" compound (DSS-Pro-Borneol), Water-soluble "Jun-Zuo-Shi" compound (Ala-Pro-N-methyl piperazine), fat-soluble "Jun-Zuo-Shi" compound (Ala-Pro-Borneol), "Jun-Zuo" compound (Ala-Pro), "Jun-Shi" compound (Pro-Borneol), "Jun-Chen" compound (DSS-Pro). By this strategy,9 target compounds and 11 intermediates were obtained. All these compounds were confirmed by 1H NMR,13C NMR and MS.(4) Nine target compounds were evaluated in inhibiting activity of ACE in vitro and in vivo. The results showed that all the compounds exhibited verious inhibiting activity of ACE. In peripheral system (kidney), the inhibition activity of Water-soluble"Jun-Chen-Zuo-Shi" compound was better than fat-soluble"Jun-Chen-Zuo-Shi" compound. The"Chen" "Zuo" and "Shi" groups also played different roles in "Jun-Chen-Zuo-Shi" compound. Especially, the results showed "Chen" group may be the more important structure among "Chen", "Zuo" and "Shi" groups.