Saccharin Aza Bioisosteres—Synthesis and Preclinical Property Comparisons

Abstract

Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster <b>B</b>), and two new types of aza-saccharins (clusters <b>C</b> and <b>D</b>). We demonstrate a convenient protocol to selectively synthesize products in cluster <b>C</b> or <b>D</b> when primary amines are used. Preclinical characterization of selected matched-pair products is reported. Through comparison of two diastereomers, we highlight how stereochemistry affects the preclinical properties. Given that saccharin-based derivatives are widely used in many chemistry fields, we foresee that structures exemplified by clusters <b>C</b> and <b>D</b> offer new opportunities for novel drug design, creating a chiral center on the sulfur atom and the option of substitution at two different nitrogens.