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

Abstract

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.

Keywords:

• Alzheimer’s disease
• semicarbazones
• acetylcholinesterase inhibitors
• NMR Kinetics
• molecular modeling
• Ellman’s test

Acknowledgments

We would like to thank the financial support afforded by the Brazilian financial agencies: CAPES, CNPq, INBEB. This work was also supported by the excellence project FIM.