One-pot Synthesis of Amino Acid-Derived Heteroaryl Ketones as Potential S. commune Metacaspase Inhibitors

Metacaspases are unique cysteine dependent proteases found exclusively in non-animal organisms, where they play a significant role in programmed cell death, or apoptosis. Metacaspases are absent in humans, making their inhibitors attractive potential drug targets for the treatment of parasitic and fungal infections. Previous work by Berg identified an arginine-derived benzothiazolyl ketone as a potent metacaspase inhibitor in T. brucei, showcasing micromolar inhibition. Demkiw demonstrated a robust one-pot Grignard-mediated synthesis of aromatic heteroaryl ketones from carboxylic acids. Building on these studies, we extend this method to amino acid-derived substrates to synthesize heteroaryl ketones as potential inhibitors of Schizophyllum commune metacaspases, an emerging fungal pathogen. Our work explores the synthetic accessibility and stereochemical outcomes of derivatives derived from diverse amino acid classes, including acidic, basic, neutral, and polar residues. This strategy provides a foundation for evaluating their inhibitory activity against fungal metacaspases.