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Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Abeta1-42 aggregation for Alzheimer's disease therapeutics.
Bioorg Med Chem. 2007 Oct 15; 15(20):6596-607.BM

Abstract

With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation.

Authors+Show Affiliations

College of Pharmacy, Woosuk University, Jeonbuk, Republic of Korea. yekwon@woosuk.ac.krNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17681794

Citation

Kwon, Young Ee, et al. "Synthesis, in Vitro Assay, and Molecular Modeling of New Piperidine Derivatives Having Dual Inhibitory Potency Against Acetylcholinesterase and Abeta1-42 Aggregation for Alzheimer's Disease Therapeutics." Bioorganic & Medicinal Chemistry, vol. 15, no. 20, 2007, pp. 6596-607.
Kwon YE, Park JY, No KT, et al. Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Abeta1-42 aggregation for Alzheimer's disease therapeutics. Bioorg Med Chem. 2007;15(20):6596-607.
Kwon, Y. E., Park, J. Y., No, K. T., Shin, J. H., Lee, S. K., Eun, J. S., Yang, J. H., Shin, T. Y., Kim, D. K., Chae, B. S., Leem, J. Y., & Kim, K. H. (2007). Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Abeta1-42 aggregation for Alzheimer's disease therapeutics. Bioorganic & Medicinal Chemistry, 15(20), 6596-607.
Kwon YE, et al. Synthesis, in Vitro Assay, and Molecular Modeling of New Piperidine Derivatives Having Dual Inhibitory Potency Against Acetylcholinesterase and Abeta1-42 Aggregation for Alzheimer's Disease Therapeutics. Bioorg Med Chem. 2007 Oct 15;15(20):6596-607. PubMed PMID: 17681794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory potency against acetylcholinesterase and Abeta1-42 aggregation for Alzheimer's disease therapeutics. AU - Kwon,Young Ee, AU - Park,Jung Youl, AU - No,Kyung Tai, AU - Shin,Jae Hong, AU - Lee,Sung Kwang, AU - Eun,Jae Soon, AU - Yang,Jae Heon, AU - Shin,Tae Yong, AU - Kim,Dae Keun, AU - Chae,Byung Sook, AU - Leem,Jae-Yoon, AU - Kim,Kuk Hwan, Y1 - 2007/07/25/ PY - 2007/05/10/received PY - 2007/06/30/revised PY - 2007/07/06/accepted PY - 2007/8/8/pubmed PY - 2007/12/7/medline PY - 2007/8/8/entrez SP - 6596 EP - 607 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 15 IS - 20 N2 - With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation. SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/17681794/Synthesis_in_vitro_assay_and_molecular_modeling_of_new_piperidine_derivatives_having_dual_inhibitory_potency_against_acetylcholinesterase_and_Abeta1_42_aggregation_for_Alzheimer's_disease_therapeutics_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(07)00619-0 DB - PRIME DP - Unbound Medicine ER -