Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors
| Autor: | José M. Padrón, Sara Montiel-Smith, José Luis Vega-Baez, Óscar López, José G. Fernández-Bolaños, Penélope Merino-Montiel, Inés Maya, Ana I Ahuja-Casarín, Miguel X. Fernandes, Irene Lagunes |
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| Přispěvatelé: | Universidad de Sevilla. Departamento de Química orgánica, Universidad de Sevilla. FQM134: Química Fina de Carbohidratos, 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 |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
docking simulations cholinesterase inhibitors biology 010405 organic chemistry Stereochemistry Chemistry Iminosugar anti-alzheimer’s agents General Medicine RM1-950 Alkylation 01 natural sciences Iminosugars 1-DNJ anti-Alzheimer’s agents 1-dnj 0104 chemical sciences 010404 medicinal & biomolecular chemistry Drug Discovery biology.protein iminosugars Therapeutics. Pharmacology Structural motif Cholinesterase |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 138-146 (2021) idUS. Depósito de Investigación de la Universidad de Sevilla instname |
| ISSN: | 1475-6374 1475-6366 |
| Popis: | 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. Dirección General de Investigación de España. CTQ2016-78703-P Junta de Andalucía. FQM134 Fondo Europeo de Desarrollo Regional (FEDER) y Consejo Nacional de Ciencia y Tecnología de México (CONACYT). CB-2015/257465 Ministerio de Ciencia, Innovación y Universidades y Agencia Estatal de Investigación de España y Fondos FEDER de la Unión Europea (MCIU/AEI/FEDER). PGC2018-094503-B-C22 |
| Databáze: | OpenAIRE |
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