Lead Optimization: Synthesis and Biological Evaluation of Griseofulvin Derivatives as Novel SIRT6 Activators

SIRT6, a crucial regulator of aging and cellular homeostasis, represents a promising target for small-molecule activation. In this study, we investigate griseofulvin and its derivatives as novel SIRT6 activators, focusing on the recently developed compound forvisirvat, which has progressed to Phase 2 clinical study. Biochemical evaluation revealed that griseofulvin itself possesses strong SIRT6-activating properties, achieving up to 10-fold activity at 100 μM. Modification of the griseofulvin scaffold generally led to reduced activity, prompting a focus on the oxadiazole moiety of forvisirvat. This strategy produced several analogues with higher potency, the most active at 100 μM being <i>para</i>-1,3,4-oxadiazolephenyl analog <b>21</b>, which achieved 30-fold SIRT6 activation. Compounds bearing <i>para</i>-substituted phenyl rings exhibited excellent retention of activity at lower concentrations, with <i>para</i>-tolyl derivative <b>24</b> being the most potent at 10 μM. Retention of activity at pharmacologically relevant concentrations underscores their potential as potent SIRT6 activators and provides a rationale for continued development as drug candidates.