title: Synthesis and cholinesterase inhibition of cativic acid derivatives.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder associated with memory impairment and cognitive deficit. Most of the drugs currently available for the treatment of AD are acetylcholinesterase (AChE) inhibitors. In a preliminary study, significant AChE inhibition was observed for the ethanolic extract of Grindelia ventanensis (IC₅₀=0.79 mg/mL). This result prompted us to isolate the active constituent, a normal labdane diterpenoid identified as 17-hydroxycativic acid (1), through a bioassay guided fractionation. Taking into account that 1 showed moderate inhibition of AChE (IC₅₀=21.1 μM), selectivity over butyrylcholinesterase (BChE) (IC₅₀=171.1 μM) and that it was easily obtained from the plant extract in a very good yield (0.15% w/w), we decided to prepare semisynthetic derivatives of this natural diterpenoid through simple structural modifications. A set of twenty new cativic acid derivatives (3-6) was prepared from 1 through transformations on the carboxylic group at C-15, introducing a C2-C6 linker and a tertiary amine group. They were tested for their inhibitory activity against AChE and BChE and some structure-activity relationships were outlined. The most active derivative was compound 3c, with an IC₅₀ value of 3.2 μM for AChE. Enzyme kinetic studies and docking modeling revealed that this inhibitor targeted both the catalytic active site and the peripheral anionic site of this enzyme. Furthermore, 3c showed significant inhibition of AChE activity in SH-SY5Y human neuroblastoma cells, and was non-cytotoxic.
authors.affiliation: INQUISUR-CONICET, Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, B8000CPB Bahía Blanca, Argentina.
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Alza
authors.affiliation: UMYMFOR (CONICET-UBA) and Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, 1428 Buenos Aires, Argentina.
authors.forename: Victoria
authors.initials: V
authors.lastname: Richmond
authors.affiliation: INIBIBB-CONICET, Instituto de Investigaciones Bioquímicas de Bahía Blanca, Camino La Carrindanga km. 7, B8000FWB Bahía Blanca, Argentina.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Baier
authors.affiliation: Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Av. Gral. Paz 1499, 1650 San Martin, Buenos Aires, Argentina; Escuela de Ciencia y Tecnología, Universidad Nacional General San Martín, Martín de Irigoyen 3100, 1650 San Martín, Buenos Aires, Argentina.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Freire
authors.affiliation: Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Av. Gral. Paz 1499, 1650 San Martin, Buenos Aires, Argentina.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Baggio
authors.affiliation: INQUISUR-CONICET, Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, B8000CPB Bahía Blanca, Argentina. Electronic address: apmurray@uns.edu.ar.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Murray
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D036623:Grindelia / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D062105:Molecular Docking Simulation
chemical_list: C000601002:17-hydroxycativic acid; D002800:Cholinesterase Inhibitors; D004224:Diterpenes; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Cholinesterase inhibitors; Diterpenoids; Labdane; Molecular modeling; SH-SY5Y neuroblastoma cells