Exploring the synthetic scope of Schizophyllum commune metacaspase I inhibitors

Metacaspases are cysteine-dependent, self-proteolytic proteases found in metazoans that facilitate metabolism, cell proliferation, and apoptosis. They are not present in mammals, making them a desirable target for anti-fungal and anti-protozoal therapeutics. Previously, an arginine derivative compound containing a heteroaryl ketone was determined to be a potent inhibitor of metacaspase II in Trypanosoma brucei, the causative agent of African sleeping sickness, by Berg et al. Later, Demkiw et al. demonstrated that heteroaryl ketones could be synthesized from carboxylic acids and bromoheterocycles in a one-pot Grignard assisted reaction. This approach has been extended to produce inhibitors for metacaspase I of Schizophyllum commune, the organism responsible for allergic bronchopulmonary mycosis. Novel syntheses extending on Demkiw's approach, its optimization, and stereospecificity will be discussed. Lead compound determination and testing will be detailed in the context of biological assays.