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Structural Consequences of the 1,2,3‐Triazole as an Amide Bioisostere in Analogues of the Cystic Fibrosis Drugs VX‐809 and VX‐770
Author(s) -
Doiron Jake E.,
Le Christina A.,
Bacsa John,
Breton Gary W.,
Martin Kenneth L.,
Aller Stephen G.,
Turlington Mark
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000220
Subject(s) - bioisostere , amide , triazole , chemistry , stereochemistry , 1,2,4 triazole , combinatorial chemistry , medicinal chemistry , chemical synthesis , organic chemistry , biochemistry , in vitro
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 R 1 and R 2 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.