Copper (II) and zinc (II) complexes with flavanone derivatives: Identification of potential cholinesterase inhibitors by on-flow assays.
Metal chelates strongly influence the nature and magnitude of pharmacological activities in flavonoids. In recent years, studies have shown that a promising class of flavanone-metal ion complexes can act as selective cholinesterase inhibitors (ChEIs), which has led our group to synthesize a new series of flavanone derivatives (hesperidin, hesperetin, naringin, and naringenin) complexed to either copper (II) or zinc (II) and to evaluate their potential use as selective ChEIs. Most of the synthesized complexes exhibited greater inhibitory activity against acetylcholinesterase (AChE) than against butyrylcholinesterase (BChE). Nine of these complexes constituted potent, reversible, and selective ChEIs with inhibitory potency (IC50) and inhibitory constant (Ki) ranging from 0.02 to 4.5μM. Copper complexes with flavanone-bipyridine derivatives afforded the best inhibitory activity against AChE and BChE. The complex Cu(naringin)(2,2'-bipyridine) (11) gave IC50and Kivalues of 0.012±0.002 and 0.07±0.01μM for huAChE, respectively, which were lower than the inhibitory values obtained for standard galanthamine (IC50=206±30.0 and Ki=126±18.0μM). Evaluation of the inhibitory activity of this complex against butyrylcholinesterase from human serum (huBChE) gave IC50and Kivalues of 8.0±1.4 and 2.0±0.1μM, respectively. A Liquid Chromatography-Immobilized Capillary Enzyme Reactor by UV detection (LC-ICER-UV) assay allowed us to determine the IC50and Kivalues and the type of mechanism for the best inhibitors.
Departamento de Química, Universidade Federal de São Carlos, Cx. Postal 676, São Carlos, 13565-905, São Paulo, Brazil.
André Lucio Franceschini
AL
Sarria
Departamento de Química, Grupo de Cromatografia de Bioafinidade e Produtos Naturais, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 14040-901, São Paulo, Brazil.
Adriana Ferreira Lopes
AF
Vilela
Departamento de Química, Grupo de Cromatografia de Bioafinidade e Produtos Naturais, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 14040-901, São Paulo, Brazil.
Bárbara Mammana
BM
Frugeri
Departamento de Química, Universidade Federal de São Carlos, Cx. Postal 676, São Carlos, 13565-905, São Paulo, Brazil.
João Batista
JB
Fernandes
Departamento de Química, Universidade Federal de São Carlos, Cx. Postal 676, São Carlos, 13565-905, São Paulo, Brazil.
Rose Maria
RM
Carlos
Departamento de Química, Universidade Federal de São Carlos, Cx. Postal 676, São Carlos, 13565-905, São Paulo, Brazil.
Maria Fátima das Graças Fernandes
MF
da Silva
Departamento de Química, Universidade Federal de São Carlos, Cx. Postal 676, São Carlos, 13565-905, São Paulo, Brazil.
Quezia Bezerra
QB
Cass
Departamento de Química, Grupo de Cromatografia de Bioafinidade e Produtos Naturais, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 14040-901, São Paulo, Brazil. Electronic address: ccardoso@ffclrp.usp.br.
Carmen Lúcia
CL
Cardoso
D000110:Acetylcholinesterase / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D047309:Flavones / Q000737:chemistry*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans
D002800:Cholinesterase Inhibitors; D056831:Coordination Complexes; D047309:Flavones; D058851:GPI-Linked Proteins; D003300:Copper; C548244:ACHE protein, human; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
Biometal-chelating agents; Cholinesterase inhibitor; Flavonoid-derivatives complexes; On-flow assay