Exploration of Novel Scaffolds Targeting Cytochrome b of Pyricularia oryzae .

The fulfilment of the European "Farm to Fork" strategy requires a drastic reduction in the use of "at risk" synthetic pesticides; this exposes vulnerable agricultural sectors-among which is the European risiculture-to the lack of efficient means for the management of devastating diseases, thus endangering food security. Therefore, novel scaffolds need to be identified for the synthesis of new and more environmentally friendly fungicides. In the present work, we employed our previously developed 3D model of cytochrome (cyt ) complex to perform a high-throughput virtual screening of two commercially available compound libraries. Three chemotypes were selected, from which a small collection of differently substituted analogues was designed and synthesized. The compounds were tested as inhibitors of the cyt enzyme function and the mycelium growth of both strobilurin-sensitive (WT) and -resistant (RES) strains. This pipeline has permitted the identification of thirteen compounds active against the RES cyt and five compounds that inhibited the WT cyt function while inhibiting the fungal mycelia only minimally. Serendipitously, among the studied compounds we identified a new chemotype that is able to efficiently inhibit the mycelium growth of WT and RES strains by ca. 60%, without inhibiting the cyt enzymatic function, suggesting a different mechanism of action.