Synergism between Terbinafine and a Neo-clerodane Dimer or a Monomer Isolated from Baccharis flabellata against Trichophyton rubrum

Abstract

The new neo-clerodane dimer (DACD) likely formed by a [4+2] photo-cycloaddition between two molecules of ent-15,16-epoxy-19-hydroxy-1,3,13(16),14-clerodatetraen-18-oic acid (DAC), both isolated from Baccharis flabellata Hook et Arn. var. flabellata (Asteraceae), were tested in combination with terbinafine (Terb) against Trichophyton rubrum. The interactions were assessed with different methodologies such as 3D CombiTool software, Loewe Combination Index (CI) and isobolograms. Results showed that the monomer DAC as well as its dimer DACD act synergistically with Terb against T. rubrum. DAC/Terb and DACD/Terb showed eight and twelve synergistic mixtures respectively in the CombiTool graphics thus suggesting that DACD/Terb was more synergistic with Terb than DAC. These results were corroborated by the CI values and the isobolograms of the detected combinations. DACD/Terb showed much lower CIs (0.34-0.47) than DAC/Terb (0.57-1.15) at the different inhibition percentages tested. Concomitantly, DACD/Terb isobolograms were more concave than for DAC/Terb at the different inhibition percentages. This is the first report showing antifungal synergistic interactions of neo-clerodanes dimers and add new evidences that neo-clerodanes monomers interact synergistically with Terb against T. rubrum.