NMR quantification of H-bond donating ability for bioactive functional groups and isosteres

The H-bond donating ability for 127 compounds including drug fragments and isosteres have been quantified using a simple and rapid method with ³¹P NMR spectroscopy. Functional groups important to medicinal chemistry were evaluated including carboxylic acids, alcohols, phenols, thioic acids and nitrogen group H-bond donors. ³¹P NMR shifts for binding to a phosphine oxide probe have a higher correlation with equilibrium constants for H-bonding (log K^H_A) than acidity (pK_a), indicating that these binding experiments are representative of H-bonding ability and not proton transfer. Additionally, ³¹P NMR binding data for carboxylic acid isosteres correlates with physicochemical properties such as lipophilicity, membrane permeability and plasma protein binding. This method has been used to evaluate the H-bond donating ability of small molecule drug compounds such as NSAIDs and antimicrobials.