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Combined Chemical, Biological and Theoretical DFT‐QTAIM Study of Potent Glycosidase Inhibitors Based on Quaternary Indolizinium Salts
Author(s) -
Šafář Peter,
Žúžiová Jozefína,
Marchalín Štefan,
Prónayová Nadežda,
Švorc Ľubomír,
Vrábel Viktor,
Šesták Sergej,
Rendić Dubravko,
Tognetti Vincent,
Joubert Laurent,
Daïch Adam
Publication year - 2012
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201200431
Subject(s) - chemistry , enantiopure drug , regioselectivity , glycoside hydrolase , stereochemistry , ring (chemistry) , selectivity , enzyme , organic chemistry , enantioselective synthesis , catalysis
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 and comparison was made to the quaternizations of other substituted indolizidines. Importantly, a combined theoretical DFT‐QTAIM study has cast light on the various factors that explain the observed conformational selectivity. The inhibitory properties of the six synthesized indolizidines were then investigated against the recombinant Golgi α‐mannosidase‐IIb (dGMIIb) and lysosomal α‐mannosidase (dLM408), human homologues of Drosophila melanogaster . Among the tested compounds, two of them, 4a and 4b , exhibited a pH‐dependent inhibition of dGMIIb at the milimolar level (IC 50 = 3.5 or 1.7 mM at pH 5.8 or 6.5, respectively) without affecting the activity of dLM408.