Combined Chemical, Biological and Theoretical DFT‐QTAIM Study of Potent Glycosidase Inhibitors Based on Quaternary Indolizinium Salts
作者： Peter Šafář , Jozefína Žúžiová , Štefan Marchalín , Nadežda Prónayová , Ľubomír Švorc
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摘要: Six novel enantiopure epimeric indolizidinediols have been easily prepared in high yields by an effective and well-established regioselective THF ring-opening reaction as a key step. Quarternization of these species was also studied comparison made to the quaternizations other substituted indolizidines. Importantly, combined theoretical DFT-QTAIM study has cast light on various factors that explain observed conformational selectivity. The inhibitory properties six synthesized indolizidines were then investigated against recombinant Golgi α-mannosidase-IIb (dGMIIb) lysosomal α-mannosidase (dLM408), human homologues Drosophila melanogaster. Among tested compounds, two them, 4a 4b, exhibited pH-dependent inhibition dGMIIb at milimolar level (IC50 = 3.5 or 1.7 mM pH 5.8 6.5, respectively) without affecting activity dLM408.
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