Kristian Sørnes

• Berntsen, Linn Neerbye; Solvi, Thomas Nordbø; Sørnes, Kristian; Wragg, David Stephen & Sandtorv, Alexander Harald (2021). Cu-catalyzed C(sp2)-N-bond coupling of boronic acids and cyclic imides. Chemical Communications. ISSN 1359-7345. 57(89), p. 11851–11854. doi: 10.1039/d1cc04356k.

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• Sørnes, Kristian & Sandtorv, Alexander Harald (2021). Altering the structural elements of indole-based PDF inhibitors: Synthesis and characterisation. Universitetet i Oslo. Show summary

  Indole-based hydroaxmic acids have previously been shown to selectively inhibit bacterial peptide deformylase (PDF), a metalloenzyme that cleaves off formyl the N-terminal end of newly formed proteins. Amino acid formylation and subsequent deformylation make up a set of processes that are crucial for bacterial growth and redundant in human cells, making PDF an intriguing antibacterial target. Inhibition of PDF represents a novel mode of action that is yet to be exploited by commercial antibiotics, something that is desparately needed in the fight against antimicrobial resistance. The existence of a human mitochondrial PDF has been a source of concern despite its role in normal cell function being largely unknown. Inhibitors that are selective towards bacterial PDF are therefore of major interest. Indole-based inhibitors are said to achieve selectivity through their central indole scaffold, which is reportedly too bulky to fit the active site of human PDF. No justification for the indole fragment has been given apart from its apparent size, raising questions around which exact structural elements are needed for selective inhibition. In this study, we sought to synthesise analogues of indole-based inhibitors with certain structural elements altered, intending to explore potential enzyme interactions that may or may not be important for inhibition. The central scaffold became the main focus of the study, for which four different synthetic routes were designed. The four target molecules included an indole benchmark and its corresponding benzimidazole, benzotriazole, and indene equivalents. Of these, only the indole and indene targets were successfully synthesised. The indole structure could be formed at poor yields using a reported procedure, while the indene structure required careful handling of a dynamic endo/exo-isomerisation. Major steps were made in the syntheses of the benzimidazole and benzotriazole targets, with both scaffolds successfully being formed as intended. Ultimately, the designed routes failed at incorporating the needed hydroxamic acid functionality. The indole and indene inhibitors remain to be tested for inhibitory activity. Future studies should focus on biochemical testing of the synthesised structures, as well as redoing the benzimidazole and benzotriazole routes using water-insoluble peptide coupling reagents in the final step. Preliminary studies were made on the formation of indolyl and indenyl hydrazides, although more purification is needed. Suggested synthetic routes for indane, naphthalene, pyridine, and thiohydoxamic acid targets are provided.

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