Design, Synthesis and Biological Activity Evaluation of Novel Indole SIRT2 Inhibitors

SIRT2, an atypical deacetylase, belongs to one of the seven subtypes of Surtuin protein, which plays an important role in the occurrence and development of cancer, neurodegenerative diseases, bacterial infections and other diseases. Nowadays, a large number of SIRT2 small molecule inhibitors have been reported one after another, but so far no inhibitor has entered clinical research. In our previous research, through rational design and synthesis, N-(1-benzyl-1H-indazol-4-yl)-2-(naphthalen-1-yloxy)acetamide(14a), a SIRT2 inhibitor with potent inhibitory activity was obtained. It has an seperately inhibition rate of 70% and 36% at 100 μmol·L⁻¹ and 10 μmol·L⁻¹. Starting from compound 14a, after replacing the N atom at the position with a C atom, 10 new N- (1 H- indole-4-yl) -2- (naphthalene -1-oxyl) acetamides derivatives were designed and synthesized. A series of rational drug design and novel indindl target compounds were designed and synthesized, and 27m of better inhibitory activity were obtained by enzyme-level activity evaluation . The research in this paper provided more new SIRT2 frameworks for the development of SIRT2 inhibitors.