The RNA-dependent transcriptase of influenza virus is an attractive antiviral target, still not addressed by any commercialized drugs. Flutimide, a fungal metabolite, comprising an unusual 2,6-diketopiperazine core has earlier been shown to inhibit the endonuclease activity of influenza transcriptase. In this paper we present a novel synthetic approach to 2,6-diketopiperazines, based on the rearrangement of 2-acyl-5-arylidene-3,5-dihydro-4H-imidazol-4-ones and synthesis and anti-influenza evaluation of a series of novel flutimide analogs. © 2014 Elsevier Ltd. All rights reserved.