Novel arylcarbamate-N-acylhydrazones derivatives as promising BuChE inhibitors: Design, synthesis, molecular modeling and biological evaluation.

Autor: Yamazaki DAS; Department of Chemistry, State University of Maringá, Maringá, PR, Brazil., Rozada AMF; Department of Chemistry, State University of Maringá, Maringá, PR, Brazil., Baréa P; Department of Chemistry, State University of Maringá, Maringá, PR, Brazil., Reis EC; Department of Chemistry, State University of Maringá, Maringá, PR, Brazil., Basso EA; Department of Chemistry, State University of Maringá, Maringá, PR, Brazil., Sarragiotto MH; Department of Chemistry, State University of Maringá, Maringá, PR, Brazil., Seixas FAV; Department of Technology, State University of Maringá, Umuarama, PR, Brazil., Gauze GF; Department of Chemistry, State University of Maringá, Maringá, PR, Brazil. Electronic address: gfgbandoch@uem.br.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 Feb 15; Vol. 32, pp. 115991. Date of Electronic Publication: 2021 Jan 02.
DOI: 10.1016/j.bmc.2020.115991
Abstrakt: A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC 50 values of 0.07-2.07 µM, highlighting the compound 10c (IC 50  = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC 50  = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH⋯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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