Sirtuins refer to a family of NAD+-dependent lysine deacetylases that is involved in the regulation of crucial cellular processes as gene transcription, apoptosis and energy metabolism. Based on a moderately active but unselective lead structure, a small set of analogous stilbenoid compounds was synthesized and examined for their influence on the deacetylase activity of the human sirtuins Sirt1–3. Furthermore, azologization yielded several phenylazopyridines and azobenzenes, whose performance as molecular photoswitches was examined in an aqueous environment. For some compounds, inhibitory activity reached the sub-micromolar range in the thermal equilibrium and could be reduced by a factor of four, when irradiated with UV-light. Interestingly, derivatization with long-chain fatty acids yielded potent Sirt2 inhibitors, whose biological activity could be induced by a light-mediated increase in aqueous solubility.