Search for Molecular Basis of Antifungal Activity of Thiosemicarbazide Derivatives: A Combined in vitro Antifungal and Enzymatic Studies with in Silico Docking

Agata      Siwek; Pawel      Staczek; Aleksandra      Strzelczyk; Joanna      Stefanska

Abstract

In this study, a combined in vitro antifungal and enzymatic studies with molecular modeling techniques are presented. Although attempts with rational design strategies have been made, the bioactivity of studied 1-substituted 4- ethoxycarbonylmethylthiosemicarbazides 1a-1g was only marginal. Among the compounds tested, antifungal response was observed only for indole derivative 1f and pyrazine derivative 1g. The most important results of the antifungal screening assay can be summarized as follows: (i) the replacement of an aryl ring in 4-arylthiosemicarbazides with a flexible chain reduces antifungal response dramatically, (ii) NH-NH-C(=S)-NH core seems to be important for antifungal activity of thiosemicarbazides. Based on docking simulations fungal secreted aspartic proteinase (SAP) was proposed as the putative enzyme target for thiosemicarbazide derivatives with a flexible chain at the N4 position of thiosemicarbazide core.

Keywords: Antifungal activity, Modeling prediction, Molecular docking, Thiohydantoine, Thiosemicarbazide, s-triazole, Candida albicans, MIC range, GNAT, N-acetyltransferase