Synthesis of Potential Small-Molecule Inhibitors for S. commune Metacaspase

Metacaspase are proteases that are involved in the cell death pathway of fungi. A better understanding of metacaspase might be helpful in the development of the antifungal drugs. The project was a collaboration between the Fox Lab and the Kehlbeck Lab. The Fox Lab aims to elucidate the structures and the properties of five types of metacaspase enzyme in S. commune fungus. The Kehlbeck Lab, has been working on synthesizing different inhibitors for the S. commune metacaspase. Z-Arg(Pmc)-benzothiazole served has been shown to inhibit similar metacaspases in similar organisms. The project aimed to propose the most effective synthetic pathway to generate Z-Arg(Pmc)-benzothiazole that would ideally allow us to explore other related inhibitors. This project focused on studying the direct one-way synthesis pathway from a carboxylic acid and heteroaryl halides. Several model reactions with different R-groups were tested and analyzed by NMR and GC-MS to study the effectiveness of the synthesis pathway. The model reaction using Z-Ala-OH gave the most promising NMR data. The NMR result suggested that a new compound, which was different from the starting materials, had been synthesized. In the near future, the synthesis method will be studied using different model reactions to compare how it works on structures with different R-groups. The final goal of the research is to make a library of different inhibitors for S.commune metacaspase.

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