Synthesis and bioassay evaluation of arginine-derived metacaspase inhibitors targeting Schizophyllum commune

Metacaspases are cysteine-dependent proteases found in fungi and protozoa but absent in humans, making them attractive antifungal drug targets. Berg and colleagues successfully identified an arginine-derived benzothiazolyl ketone as a potent metacaspase inhibitor in T. brucei. We are interested in identifying inhibitors for S. commune metacaspases as tools to better understand activity and with potential to determine the structure of S. commune metacaspases. We have extended Demkiw's multi-component Grignard-based strategy previously reported for aryl carboxylic acids to protected amino acids, thereby generating a library of heteroaryl ketones as potential inhibitors for S. commune metacaspases. Herein, we report the results of bioassays to compare relative potencies of synthesized inhibitor candidates. This study provides insights into the synthesis of potential S. commune metacaspase inhibitors consisting of stereochemically defined heteroaryl ketones, and a framework for correlating chemical structure with inhibitory potential in S. commune.