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

## TL;DR

Scientists developed and tested new versions of a drug called griseofulvin that can activate a protein important for aging and cell health, with some showing strong effects even at low doses.

## Contribution

The study introduces novel griseofulvin derivatives with enhanced SIRT6 activation at pharmacologically relevant concentrations.

## Key findings

- Griseofulvin itself activates SIRT6 up to 10-fold at 100 μM.
- The para-1,3,4-oxadiazolephenyl analog 21 achieves 30-fold SIRT6 activation at 100 μM.
- Para-tolyl derivative 24 shows potent SIRT6 activation at 10 μM.

## Abstract

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 para-1,3,4-oxadiazolephenyl analog 21, which achieved 30-fold SIRT6 activation. Compounds bearing para-substituted phenyl rings exhibited excellent retention
of activity at lower concentrations, with para-tolyl
derivative 24 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.