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

<p>Two new compounds (<i>E</i>)-2-(5,7-dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2<i>H</i>)-ylidene)hydrazinecarbothiomide (<b>3</b>) and (<i>E</i>)-2-(5,7-dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2<i>H</i>)-ylidene)hydrazinecarboxamide (<b>4</b>) were synthesized and evaluated for their anticholinesterase activities. <i>In vitro</i> 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, <i>in silico</i> toxicity evaluation suggested that these new compounds can be less toxic than tacrine.</p>