Structural Consequences of the 1,2,3‐Triazole as an Amide Bioisostere in Analogues of the Cystic Fibrosis Drugs VX‐809and VX‐770

Although the 1,2,3‐triazole is a commonly used amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X‐ray crystallography and computational studies, we report the spatial and electronic consequences of replacing an amide wit...

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Bibliographic Details
Published in:ChemMedChem 2020-09, Vol.15 (18), p.1720-1730
Main Authors: Doiron, Jake E, Le, Christina A, Bacsa, John, Breton, Gary W, Martin, Kenneth L, Aller, Stephen G, Turlington, Mark
Format: Article
Language:English
Subjects:
Chemists
Computer applications
Crystallography
Cystic fibrosis
Drugs
Hydrogen bonding
Spatial analysis
Triazoles
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Summary:Although the 1,2,3‐triazole is a commonly used amide bioisostere in medicinal chemistry, the structural implications of this replacement have not been fully studied. Employing X‐ray crystallography and computational studies, we report the spatial and electronic consequences of replacing an amide with the triazole in analogues of cystic fibrosis drugs in the VX‐770 and VX‐809 series. Crystallographic analyses quantify subtle differences in the relative positions and conformational preferences of the R1 and R2 substituents attached to the amide and triazole bioisosteres. Computational studies derived from the X‐ray data highlight the improved hydrogen bonding donor and acceptor capabilities of the amide in comparison to the triazole. This analysis of the spatial and electronic differences between the amide and 1,2,3‐triazole will inform medicinal chemists as they consider using the triazole as an amide bioisostere.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202000220