Design of Multi-Target Compounds as AChE, BACE1, and Amyloid-β_1-42 Oligomerization Inhibitors: In Silico and In Vitro Studies

Article type: Research Article

Authors: Hernández-Rodríguez, Maricarmen^{a; b} | Correa-Basurto, José^a | Martínez-Ramos, Federico^c | Padilla-Martínez, Itzia Irene^d | Benítez-Cardoza, Claudia G.^e | Mera-Jiménez, Elvia^f | Rosales-Hernández, Martha Cecilia^{b; *}

Affiliations: [a] Laboratorio de Modelado Molecular y Diseño de Fármacos, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México, D.F. | [b] Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México, D.F. | [c] Laboratorio de Investigación Departamento de Química Inorgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México, D.F. | [d] Laboratorio de Investigación en Química Orgánica y Supramolecular, Unidad Profesional Interdisciplinaria de Biotecnología del Instituto Politécnico Nacional. Av. Acueducto s/n Barrio la Laguna Ticomán, México, D.F. | [e] Laboratorio de Investigación Bioquímica, Sección de Estudios de Posgrado e Investigación, ENMyH-Instituto Politécnico Nacional, La Escalera Ticoman, México, D.F. | [f] Laboratorio de Cultivo Celular, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, México, D.F.

Correspondence: [*] Correspondence to: Martha Cecilia Rosales-Hernández, Laboratorio de Biofísica y Biocatálisis, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 México, D.F. Tel: +55 57296000/Ext. 62767 and 62809; Fax: +55 57296000/Ext. 62806; E-mails: [email protected]; [email protected].

Abstract: Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.

Keywords: Acetylcholinesterase, Alzheimer's disease, amyloid-β, β-site AβPP cleaving enzyme 1, inhibitor

DOI: 10.3233/JAD-140471

Journal: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1073-1085, 2014