title: Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease.
abstract: Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 μM, and a similar inhibition profile of the human isoform (IC50 = 5.7 μM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 μM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.
authors.affiliation: Department of Pharmacy, Health Sciences Faculty, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil; LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil.
authors.forename: Laís Flávia Nunes
authors.initials: LFN
authors.lastname: Lemes
authors.affiliation: Department of Pharmacy, Health Sciences Faculty, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil; LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil.
authors.forename: Giselle
authors.initials: G
authors.lastname: de Andrade Ramos
authors.affiliation: Department of Pharmacy, Health Sciences Faculty, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil; LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil.
authors.forename: Andressa Souza
authors.initials: AS
authors.lastname: de Oliveira
authors.affiliation: Biomedical Sciences Institute (ICB), Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Fernanda Motta R
authors.initials: FMR
authors.lastname: da Silva
authors.affiliation: Biomedical Sciences Institute (ICB), Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Gina
authors.initials: G
authors.lastname: de Castro Couto
authors.affiliation: Biomedical Sciences Institute (ICB), Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Marina
authors.initials: M
authors.lastname: da Silva Boni
authors.affiliation: Biomedical Sciences Institute (ICB), Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Marcos Jorge R
authors.initials: MJR
authors.lastname: Guimarães
authors.affiliation: Biomedical Sciences Institute (ICB), Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Isis Nem O
authors.initials: INO
authors.lastname: Souza
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.affiliation: Department for Life Quality Studies, University of Bologna, Corso D'Augusto 237, 47921, Rimini, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.affiliation: CENAUREMN, Department of Organic and Inorganic Chemistry, Federal University of Ceará, 60021-970, Fortaleza, CE, Brazil.
authors.forename: Patrícia Coelho
authors.initials: PC
authors.lastname: do Nascimento Nogueira
authors.affiliation: CENAUREMN, Department of Organic and Inorganic Chemistry, Federal University of Ceará, 60021-970, Fortaleza, CE, Brazil.
authors.forename: Edilberto Rocha
authors.initials: ER
authors.lastname: Silveira
authors.affiliation: Chemistry Institute, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil.
authors.forename: Guilherme D
authors.initials: GD
authors.lastname: Brand
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; National Institute of Mental Health, Topolová 748, 250 67, Klecany, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; National Institute of Mental Health, Topolová 748, 250 67, Klecany, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Korábečný
authors.affiliation: LICC - Laboratório Integrado de Computação Científica, NUPEM, Federal University of Rio de Janeiro, 27901-000, Macaé, RJ, Brazil.
authors.forename: Nelilma C
authors.initials: NC
authors.lastname: Romeiro
authors.affiliation: Biomedical Sciences Institute (ICB), Federal University of Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Newton G
authors.initials: NG
authors.lastname: Castro
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: marialaura.bolognesi@unibo.it.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
authors.affiliation: Department of Pharmacy, Health Sciences Faculty, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil; LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil. Electronic address: luizromeiro@unb.br.
authors.forename: Luiz Antonio Soares
authors.initials: LAS
authors.lastname: Romeiro
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D001665:Binding Sites / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010636:Phenols; C038590:cardanol; D002802:Cholinesterases
keywords: Acetylcholinesterase; Alzheimer's disease; Cashew nut shell liquid; Dual binding site AChE inhibitors; Multitarget compounds