Structural Consequences of the 1,2,3‐Triazole as an Amide Bioisostere in Analogues of the Cystic Fibrosis Drugs VX‐809 and 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 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. A question of equality: The 1,2,3‐triazole is commonly used as an amide surrogate in medicinal chemistry. However, comparing the positional and electronic features of the bioisosteres reveals notable differences in the relative positioning of their R1 and R2 groups and their hydrogen bonding capability. This analysis will inform medicinal chemists considering using the triazole to replace an amide linkage.