Glucocorticoids (GCs) are commonly used as anti-inflammatory and immunosuppressant medications for the treatment of a variety of diseases such as rheumatoid arthritis, certain types of cancer, and organ/tissue transplantation through transrepression activities. Chronic GC use has been linked with untoward complications such as Steroid Induced Diabetes Mellitus (SIDM), potentially through dimerization of the Glucocorticoid Receptor (GR) and subsequent transactivation. Modification of clinically used GC with an array of mercapto- moieties at the C21 site resulted in consistently reduced promoter activity in the 3xGRE assays associated with transactivation while maintaining the desired decrease in IL-1β associated with transrepression. Derivatization with a furoyl ester to the GC backbone had the opposite effect by reintroducing promoter activity associated with transactivation. The addition of an aryl pyrazole moiety to hydrocortisone displayed up to 90% anti-inflammatory response at 0.1 nM while dexamethasone showed only 30% response at this concentration. The top performing candidate, dexamethasone mercaptobenzothiazole<b> (2a)</b>, demonstrated a significant 87% reduction in transactivation when compared with commercially available dexamethasone. To further explain these results, Molecular Dynamic (MD) simulations were performed on all compounds to examine structural changes in the Ligand Binding Domain (LBD) of the GR in response to docking with each ligand. Results revealed that <b>2a</b> displays two unique, simultaneous pi-stacking interactions with Phe740 and Phe749. These findings provide novel insights into the structure-activity relationships that are likely to be important for clinical utility.

Glucocorticoids modified with mercapto- moieties display an improved safety profile compared with their clinically administered parent molecules

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