Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry

Irene Lagunes¹  José M. Padrón¹  Miguel X. Fernandes¹  José G. Fernández-Bolaños²  Óscar López²  Inés Maya²  Penélope Merino-Montiel³  Sara Montiel-Smith³  Ana I. Ahuja-Casarín³  José Luis Vega-Baez³ 

[1] BioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Universidad de La Laguna;Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla;Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla;

关键词: iminosugars;    1-dnj;    cholinesterase inhibitors;    anti-alzheimer’s agents;    docking simulations;   

DOI  :  10.1080/14756366.2020.1847101

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown