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 ), and two new types of aza-saccharins (clusters and ). We demonstrate a convenient protocol to selectively synthesize products in cluster or 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 and offer new opportunities for novel drug design, creating a chiral center on the sulfur atom and the option of substitution at two different nitrogens.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467200 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.7b00137 | DOI Listing |
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