Synthesis And Ache, Buche Inhibitory Activity Of Deoxyvasicinone Derivatives

Alzheimer’s Disease is a neurodegenerative diseases commonly happened among the elderly, firstly recognized as selective loss of cholinergic neurons in the root of forebrain. The symptom of AD is the lost of progressive memory and language ability, recognize ability obstacles, which is deteriorating and then disrupt daily life gradually until death. Cholinesterase(acetylcholin esterase ACh E, butyrylcholine esterase Bu Ch E) inhibitors are effective drugs treating AD. ACh E inhibitor and Bu Ch E inhibitor are both significant to the treatment of AD, which means that compounds balanced inhibit ACh E and Bu Ch E can be effective drugs for the treatment of AD. Researches have shown that methanlol extracts of seed of peganum harmala deoxyvasicinone contained exhibit obvious ACh E inbihitory activity. Connecting suitable substitute groups to the 7-position of deoxyvasicinone is of great help to improve the ACh E, Bu Ch E inhibitory activity. In this research, we link N-atom to the 7-position of dexoyvasicinone and increase the joining chain through the amino acid to obtain deoxyvasicinone derivatives and the ACh E,Bu Ch E inhibitory activity of those compounds have been tested to find a potential drug to treat AD. Besides, the structure-function relationship is discussed to lay solid foundation for later research. The results of those studies are as follows:1, Deoxyvasicinone and its analogues(vasicinone, vasicine, and deoxyvacine) have been identified that they have ACh E, Bu Ch E inhibitory activity, however, the IC50 have not been discussed. In this study, those four natural alkaloids are separated and the IC50 of ACh E, Bu Ch E are measured.2, Deoxyvasicinone has been synthesized starting from o-aminobenzoic acid through witting reaction. Then, after four steps(nitration, amino reduction, condensation, nucleophilic substitution with different bromo-compounds), nineteen ramifications are obtained, all of which are new compounds. Structures of those compounds have been identified with the help of 1H NMR、13C NMR、ESI-MS. Meanwhile, the physical properties are measured. 3, ACh E, Bu Ch E inhibitory activity of those nineteen compounds are measured through Ellman colorimetric method taking tacrine as positive control and the IC50 are calculated. According to the results, compared to deoxyvasicinone, all those synthetic compounds showed better ACh E, Bu Ch E inhibitory activity with the IC50 lower than 10 μM. Thirteen of nineteen exhibited better ACh E inhibitory activity than positive control with the IC50(ACh E) =46.5 n M; Ten compounds revealed balanced inhibitory activity towards ACh E and Bu Ch E. According to the results of the ACh E, Bu Ch E inhibitory activity test, T-7(IC50(ACh E) =46.4 n M, IC50(Bu Ch E) =12.4 n M), T-8(IC50(ACh E) =25.9 n M, IC50(Bu Ch E) =16.3 n M), T-11(IC50(ACh E)=21.2 n M, IC50(Bu Ch E)=10.7 n M), T-12(IC50(ACh E)=25.3 n M, IC50(Bu Ch E)=36.7 n M), T-16(IC50(ACh E)=5.31 n M, IC50(Bu Ch E)=4.3 n M), T-22(IC50(ACh E)=7.61 n M, IC50(Bu Ch E)=2.35 n M) exhibited potent inhibitory activity. T-16 showed the most potent activity.4, Preliminary structure-activity relationship showed: most ramifications revealed more potent ACh E, Bu Ch E inhibitory activity than deoxyvasicinone. As a whole, compounds with aliphatic series substitute groups had better ACh E, Bu Ch E inhibitory activity than compounds with aromatic substitute groups. Among derivatives with aromatic substitute groups, T-22 showed the most potent inhibitory activity; among derivatives with aliphatic series substitute groups, T-16 was the best.According to the above researches, synthetic compounds exhibited potent and balanced ACh E, Bu Ch E inhibitory activity. Several ramifications had much more strong inhibitory activity than deoxyvasicinone, which obtained great research value.