1、New Dual Binding Site Inhibitors of AChE,Chen Linyao Jiang Pei Lv Hongbin,Contents,Conclusion,References,Comparison of articles,Introduction,Introduction,Alzheimers disease (AD) is the most common form of Dementia. It is a progressive, degenerative disorder of the brain characterised by loss of memo
2、ry and cognition. Current treatment approaches in this disease continue being primarily symptomatic,with the major therapeutic strategy based on the cholinergic hypothesis and specifically on AChE inhibition,AChE inhibitors able to interact with CAS(catalysis active site)，make the ACh cannot be hydr
3、olyzed, while the ones able to interact with PAS(peripheral anionic site) can prevent synthesis, deposition and aggregation of toxic AThus the dual-binding inhibitors target simultaneously both the CAS and the PAS will be selective and potent AChE inhibitors .,1. Acetylcholinesterase: How is structu
4、re related to function? Israel Silmana, Joel L. Sussmanb,.,2. Donepeziltacrine hybrid related derivatives as new dual binding site inhibitors of AChED. Alonso, I. Dorronsoro,L. Rubio, P. Munoz, E. Garca-Palomero,A new series of donepeziltacrine hybrid related derivatives have been synthesised as dua
5、l AchE inhibitors that could bind simultaneously to the PAS and CAS of the enzyme. These new hybrids combined a tacrine unit as catalytic binding site and indanone (the heterocycle present in donepezil) as peripheral binding site of the enzyme, connected through a different linker tether length.,Rep
6、resentation of this compound docked into the binding site of AChE and it emerged as a potent and selective AChE inhibitor,3. 2-Phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors Yanhong Shen Rong Sheng , Jing Zhang Qiaojun He , Bo Yang , Yongzhou Hu,Aiming at developing new agents of
7、 potential application in AD, a new series of 2-phenoxy-indan-1-one derivatives which possess alkylamine side chain were designed, synthesized and evaluated for their inhibitory activity against AChE and BuChE. Most of the compounds were found to inhibit AChE in the nanomolar range. The optimum inhi
8、bitor exhibited 34-fold increase in AChE inhibition than donepezil and displayed neuroprotective effect against H2O2-induced cell death.,Interaction between the compound and AChE.,4. Design and synthesis of tacrineferulic acid hybrids as multi-potent anti-Alzheimer drug candidates Lei Fang, Birgit K
9、raus,Jochen Lehmann, Joerg Heilmann, Yihua Zhang, and Michael Deckera,Five tacrineferulic acid hybrids were designed and synthesized as multi-potent anti-Alzheimer drug candidates.All target compounds have better AChE inhibitory activity and comparable BuChE inhibitory activity in relation to tacrin
10、e. Interestingly, they also showed a reversible and non-competitive inhibitory action for AChE indicating interaction with the PAS, whereas a reversible but competitive inhibitory action for BuChE.,+,5. Design, synthesis and evaluation of galanthamine derivatives as acetylcholinesterase inhibitorsPi
11、ng Jia a, Rong Sheng , Jing Zhang , Liang Fang , Qiaojun He , Bo Yang , Yongzhou Hu,A series of bivalent galanthamine derivatives were designed, synthesized and evaluated as AChE inhibitors. Structure-activity studies showed that the potency of AChE inhibition was mainly influenced by the function a
12、t the end of the chain, as well as the length of the connecting units,6. New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase,calcium entry, and exhibit neuroprotection properties Rafael Len , Cristbal de los Ros , Jos Marco-Contelles , Oscar Huertas , Xavier Barril ,F. Javier Luque
13、 , Manuela G. Lpez , Antonio G. Garca , Mercedes Villarroya,In this communication, a series of new tacrine-1,4-dihydropyridine hybrids bearing the general structure of 11-amino-12-aryl-3,3-dimethyl-3,4,5,7,8,9,10,12-octahydrodibenzob,g1,8naphthyridine-1(2H)-one were synthesised. These multifunctiona
14、l compounds are moderately potent and selective AChEIs, with no activity toward BuChE. And the new compounds preferentially bind the peripheral anionic site of AChE.,Conclusion,The structure-activity relationship of acetylcholinesterase will lay the foundation for the research of new dual binding si
15、te inhibitors of AChE.so we can bring about even more potent and selevtive inhibitors with improved therapeutic action on AD.,References,Israel Silman, Joel L. Sussman . Acetylcholinesterase: How is structure related to function? Chemico-Biological Interactions 175 (2008) 310 Alonso D , Dorronsoro I
16、 , Rubio L , et al . Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE J . Bioorg Med Chem , 2005 , 13 (24) : 6588-6597 Yanhong Shen Rong Sheng , Jing Zhang ,Qiaojun He , Bo Yang , Yongzhou Hu. 2-Phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitor
17、s. Bioorganic & Medicinal Chemistry 16 (2008) 76467653,Lei Fang, Birgit Kraus, Jochen Lehmann, Joerg Heilmann, Yihua Zhang, and Michael Decker .Design and synthesis of tacrineferulic acid hybrids as multi-potent anti-Alzheimer drug candidates Bioorganic & Medicinal Chemistry Letters 18 (2008) 290529
18、09 Ping Jia a, Rong Sheng , Jing Zhang , Liang Fang , Qiaojun He , Bo Yang , Yongzhou Hu . Design, synthesis and evaluation of galanthamine derivatives asacetylcholinesterase inhibitors. European Journal of Medicinal Chemistry 44 (2009) 772-784,Rafael Len, Cristbal de los Ros, Jos Marco-Contelles, Oscar Huertas, Xavier Barril, F. Javier Luque, Manuela G. Lpez, Antonio G. Garca, Mercedes Villarroya. New tacrine-dihydropyridine hybrids that inhibit acetylcholinesterase, calcium entry, and exhibit neuroprotection properties. Bioorganic & Medicinal Chemistry 16 (2008) 77597769,Thank You !,
