New semicarbazones as gorge-spanning ligands of acetylcholinesterase and potential new drugs against Alzheimer's disease: Synthesis, molecular modeling, NMR, and biological evaluation

• Published in: Journal of biomolecular structure & dynamics Vol. 36; no. 15; pp. 4099 - 4113
• Main Authors: Ferreira Neto, Denise Cristian, Alencar Lima, Josélia, Sobreiro Francisco Diz de Almeida, Joyce, Costa França, Tanos Celmar, Jorge do Nascimento, Claudia, Figueroa Villar, José Daniel
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 18-11-2018
• Subjects: Acetylcholinesterase - chemistry; acetylcholinesterase inhibitors; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer Disease - physiopathology; Alzheimer's disease; Catalytic Domain; Drug Design; Ellman's test; Enzyme Assays; Gene Expression; Humans; Hydrogen Bonding; Kinetics; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; molecular modeling; NMR Kinetics; Nootropic Agents - chemical synthesis; Nootropic Agents - pharmacology; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; semicarbazones; Semicarbazones - chemical synthesis; Semicarbazones - pharmacology; Tacrine - pharmacology; Thermodynamics; semicarbazones; NMR Kinetics; acetylcholinesterase inhibitors; Alzheimer’s disease; molecular modeling; Ellman’s test
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2017.1407676

Two new compounds (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2H)-ylidene)hydrazinecarbothiomide (3) and (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2H)-ylidene)hydrazinecarboxamide (4) were synthesized and evaluated for their anticholinesterase activities. In vitro tests performed by NMR and Ellman's tests, pointed to a mixed kinetic mechanism for the inhibition of acetylcholinesterase (AChE). This result was corroborated through further docking and molecular dynamics studies, suggesting that the new compounds can work as gorge-spanning ligands by interacting with two different binding sites inside AChE. Also, in silico toxicity evaluation suggested that these new compounds can be less toxic than tacrine.