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

Structural Consequences of the 1,2,3-Triazole as an Amide Bioisostere in Analogs of Cystic Fibrosis Drugs VX-809 and VX-770. ChemMedChem. 2020 May 08;: Authors: Doiron JE, Le CA, Bacsa J, Breton GW, Martin KL, Aller SG, Turlington M Abstract While the 1,2,3-triazole is a commonly utilized 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 the amide with the triazole in analogs 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 utilizing the triazole as an amide bioisostere. PMID: 32385907 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research