Design, synthesis, and evaluation of benzoxathiolone derivatives as monoamine oxidase inhibitors and antibacterial agents

Abstract Benzoxathiolone derivatives have in vitro activity against monoamine oxidase A (MAO-A) and MAO-B, making them potential lead compounds for the treatment of neuropsychiatric and neurodegenerative disorders. They also have antibacterial activity against numerous bacteria. The aim of this study was to synthesise two series of benzoxathiolone derivatives with different ester (series 1) and sulfonic ester (series 2) substitutions on position C6. The in vitro half-maximal inhibitory concentration (IC50) of these derivatives was determined against both MAO-A and MAO-B, after which their mode of inhibition was determined by constructing Lineweaver-Burk graphs. Additionally, the minimum inhibitory concentration (MIC) of these derivatives was also determined against Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. All derivatives had activity against both MAO-A and MAO-B. With regards to MAO-A, derivatives 1c (0.054 µM), 1f (0.052 µM), and 2a (0.072 µM) were the most active. The positive control, harmine (0.003 µM), was however more active. With regards to MAO-B, derivatives 2a (0.001 µM), 2b (0.003 µM), 2c (0.010 µM) and 2d (0.012 µM), were more active than both positive controls, i.e., safinamide (0.088 µM) and isatin (2.80 µM). Comparing the activity of the derivatives against MAO-A versus MAO-B, the sulfonic ester derivatives were more active against MAO-A while the ester derivatives were more active against MAO-B. Halide substituents on the phenyl ring notably increased MAO-A activity. For MAO-B, enhanced activity was specifically observed with para-position substitution on the ester derivatives. As for the antibacterial assays, only 1d (16 µg/ml) had activity against S. aureus.