Discovery of Halogenated Benzothiadiazine Derivatives with Anticancer Activity

Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine-based anti-hypoglycemic diazoxide. Herein, we study the structure-activity relationship of benzothiadiazine derivatives for CII inhibition for the first time. A number of more potent derivatives were identified. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with greater anticancer effect than the parent; two benzothiadiazine derivative classes (24a-d and 30a, 30c, 30d) that possess activity to reduce the cell viability of 22Rv1 prostate cancer cells and five novel 7-fluorobenzothiadiazine derivatives which possessed significant cytotoxicity in a cellular model of triple negative breast cancer. No correlation between cytotoxicity and CII inhibition was found, indicating an as yet undefined mechanism of action of this scaffold.