A series of achiral indole analogues of the selective sirtuin inhibitor EX-527 (a racemic, substituted 1,2,3,4 tetrahydrocarbazole) was designed to stabilize the bioactive conformation, and synthesized. These new indoles were evaluated against the isolated sirtuin enzymes SIRT1 and SIRT2, and against a panel of nine human cell lines. Structure-activity relationship studies demonstrated the influence of the substituent at position 3 of the indole. The most potent SIRT1 inhibitor 3h, bearing an isopropyl substituent, was as potent as EX-527, and more selective for SIRT1 over SIRT2. Compound 3g, bearing a benzyl substituent, inhibited both sirtuins at micromolar concentration and was more cytotoxic than EX-527 on several cancer cell lines.