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Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds.
J Med Chem. 2009 Sep 10; 52(17):5365-79.JM

Abstract

Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.

Authors+Show Affiliations

Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.No 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 availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19663388

Citation

Camps, Pelayo, et al. "Pyrano[3,2-c]quinoline-6-chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and Beta-amyloid-directed anti-Alzheimer Compounds." Journal of Medicinal Chemistry, vol. 52, no. 17, 2009, pp. 5365-79.
Camps P, Formosa X, Galdeano C, et al. Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds. J Med Chem. 2009;52(17):5365-79.
Camps, P., Formosa, X., Galdeano, C., Muñoz-Torrero, D., Ramírez, L., Gómez, E., Isambert, N., Lavilla, R., Badia, A., Clos, M. V., Bartolini, M., Mancini, F., Andrisano, V., Arce, M. P., Rodríguez-Franco, M. I., Huertas, O., Dafni, T., & Luque, F. J. (2009). Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds. Journal of Medicinal Chemistry, 52(17), 5365-79. https://doi.org/10.1021/jm900859q
Camps P, et al. Pyrano[3,2-c]quinoline-6-chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and Beta-amyloid-directed anti-Alzheimer Compounds. J Med Chem. 2009 Sep 10;52(17):5365-79. PubMed PMID: 19663388.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds. AU - Camps,Pelayo, AU - Formosa,Xavier, AU - Galdeano,Carles, AU - Muñoz-Torrero,Diego, AU - Ramírez,Lorena, AU - Gómez,Elena, AU - Isambert,Nicolás, AU - Lavilla,Rodolfo, AU - Badia,Albert, AU - Clos,M Victòria, AU - Bartolini,Manuela, AU - Mancini,Francesca, AU - Andrisano,Vincenza, AU - Arce,Mariana P, AU - Rodríguez-Franco,M Isabel, AU - Huertas,Oscar, AU - Dafni,Thomai, AU - Luque,F Javier, PY - 2009/8/12/entrez PY - 2009/8/12/pubmed PY - 2009/9/26/medline SP - 5365 EP - 79 JF - Journal of medicinal chemistry JO - J Med Chem VL - 52 IS - 17 N2 - Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/19663388/Pyrano[32_c]quinoline_6_chlorotacrine_hybrids_as_a_novel_family_of_acetylcholinesterase__and_beta_amyloid_directed_anti_Alzheimer_compounds_ L2 - https://doi.org/10.1021/jm900859q DB - PRIME DP - Unbound Medicine ER -