Artículo
Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors
Autor/es | Ahuja Casarín, Ana I.
Merino Montiel, Penélope Vega Báez, José Luis Montiel Smith, Sara Fernandes, Miguel X, Lagunes, Irene Maya Castilla, Inés López López, Óscar Fernández-Bolaños Guzmán, José María |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2021 |
Fecha de depósito | 2022-04-08 |
Publicado en |
|
Resumen | We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with ... We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach. |
Agencias financiadoras | Dirección General de Investigación (DGI). España Junta de Andalucía European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) Consejo Nacional de Ciencia y Tecnología (CONACYT). México Ministerio de Ciencia, Innovación y Universidades (MICINN). España Agencia Estatal de Investigación. España |
Identificador del proyecto | CTQ2016-78703-P
FQM134 CB-2015/257465 PGC2018-094503-B-C22 |
Cita | Ahuja Casarín, A.I., Merino Montiel, P., Vega Báez, J.L., Montiel Smith, S., Fernandes, M.X., Lagunes, I.,...,Fernández-Bolaños Guzmán, J.M. (2021). Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 36 (1), 138-146. |
Ficheros | Tamaño | Formato | Ver | Descripción |
---|---|---|---|---|
14756366.2020.pdf | 1.924Mb | [PDF] | Ver/ | |