Total synthesis is a key technology in drug discovery and can play an important role in structure elucidation. Many biologically active natural products are isolated in small amounts making comprehensive testing and structure determination challenging. Total synthesis of natural products enables the production of higher amounts of material to support comprehensive biological evaluation (de Vries et al., 2021) as well as structural analysis (Boehlich, 2020) or MoA studies. Our synthesis strategy aspires to be ecologically and economically benign, avoiding unnecessary protecting groups, synthetic steps, and toxic reagents (Boehlich, 2019; de Vries, 2021). Optimization of synthetic transformations, use of starting materials from natural resources and recyclable chromatographic material will enable the sustainable production of the compounds. We will initially focus on the synthesis of biarylic compounds with known fungal BET bromodomain affinity, using I-BET726 as a promising lead structure with moderate antifungal activity against Candida species (Wei, 2023). As the program progresses, we will include advanced hit candidates generated by collaborator groups as lead structures of interest for total synthesis. As a second approach, we will investigate diaryl ether and their thioether analogues, a compound class we have worked with which disrupts biofilm formation (Gudzuhn, 2022), although the mechanism of action is not yet clear and the effect on P. aeruginosa bio films has yet to be explored. Our work will be supported by the Kirchmair group to optimize ADMET properties. We will also work with other groups to perform NMR target validation with our synthesized compounds and for activity testing.

State-of-the-art synthetic methods ((organo-)catalysis, biomimetic synthesis, chiral pool), microwave synthesis, MPLC, green chemistry.