Copper (II) and zinc (II) complexes with flavanone derivatives: Identification of potential cholinesterase inhibitors by on-flow assays

• Published in: Journal of inorganic biochemistry 2016-11, Vol.164, p.141-149
• Main Authors: Sarria, André Lucio Franceschini, Vilela, Adriana Ferreira Lopes, Frugeri, Bárbara Mammana, Fernandes, João Batista, Carlos, Rose Maria, da Silva, Maria Fátima das Graças Fernandes, Cass, Quezia Bezerra, Cardoso, Carmen Lúcia
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - chemistry; Biometal-chelating agents; Butyrylcholinesterase - chemistry; Cholinesterase inhibitor; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Copper - chemistry; Flavones - chemistry; Flavonoid-derivatives complexes; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - chemistry; Humans; On-flow assay
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.09.010

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 IC50 and Ki values 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 IC50 and Ki values 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 IC50 and Ki values and the type of mechanism for the best inhibitors. Synthesis of 17 flavanone–metal complexes and their subsequent evaluation by A Liquid Chromatography-Immobilized Capillary Enzyme Reactor-by UV detection (LC-ICER-UV) assay methodology indicated that nine of these complexes exhibited high acetylcholinesterase (AChE) inhibitory activity. [Display omitted] •17 flavanone derivatives complexed to either copper or zinc were synthesized.•The inhibitory enzyme activities were evaluated by an on-flow assay methodology.•Human acetylcholinesterase and from electric eel, and butyrylcholinesterase were tested.•IC50 and Ki values and inhibitory mechanisms for the best compounds were calculated.•Compound (11) showed the highest inhibitory activity for human acetylcholinesterase.