Average Electron Density: A Quantitative Tool for Evaluating Non-Classical Bioisosteres of Amides.

Bioisosterism is strategically used in drug design to enhance the pharmacokinetic and pharmacodynamic properties of therapeutic molecules. The average electron density (AED) tool has been used in several studies to quantify similarities among nonclassical bioisosteres of carboxylic acid. In this study, the AED tool is used to quantify the similarities among nonclassical bioisosteres of an amide group. In particular, amide-to-1,2,3-triazole bioisosterism is considered. To evaluate the AED differences exhibited by isomers of nonclassical bioisosteres, both isomers of amide ( and ) and 1,2,3-triazole (1,4 and 1,5 disubstituted moieity) were considered. The amide and 1,2,3-triazole bioisosteric moieties were capped with various R groups (= methyl, hydrogen, and chloro) to account for changes in their environment. Amide-to-triazole bioisosteric substitutions were then explored in a more realistic environment, that is, within the FDA-approved anticancer imatinib drug. The AED tool effectively identified similarities between substantially different moieties, 1,2,3-triazole and amide, showing AED differences of no more than 4%. The AED tool was also proven to be useful in evaluating the contribution of various factors affecting triazole-amide bioisosterism including isomerism and changes in their environment. The AED values of each bioisostere were transferable within a maximum difference of 2.6%, irrespective of the change in environment. The 1,4- and 1,5-disubstituted isomers of 1,2,3-triazole have AED values that differ by less than unity, 0.52%. Similarly, the AED values of the - and -amide isomers differ by only 1.31%. Overall, the AED quantitative tool not only replicated experimental observations regarding similarities in bioisosteres, but also explained and quantified each contributing factor. This demonstrates the extended utility of the AED tool from nonclassical carboxylic acid bioisosteres to amide equivalents.On the contrary, electrostatic potential maps, usually used in the literature to qualitatively evaluate bioisosterism, were not similar for the 1,2,3-triazole and amide bioisosteres, under different environments. Overall, the AED tool proves to be powerful in quantitatively evaluating and predicting bioisosterism across diverse moieties considering structural and environmental variations, making it valuable in drug design.