Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents.

This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.

Design and characterization of a new miniaturized rotating disk equipment for in vitro dissolution rate studies.

A miniaturized apparatus for the determination of the apparent in vitro dissolution rate has been designed, constructed and characterized. The miniaturized apparatus was based on a low volume dissolution cell and a disk in a rotating magnetic bar. The disk tablet is pressed directly into the bar with a press designed and constructed for this purpose. It requires approximately 5 mg of substance. The disk was positioned eccentrically on the bar with an external flow of medium to increase the rate of solvent flow over the disk surface. Six different drug substances were used. The dissolution media were sodium phosphate buffer, pH 7.0, and ammonium acetate buffer, pH 6.8. All quantifications were made by integrating the dissolution cell with high-performance liquid chromatography (HPLC) using diode-array detection (DAD). The obtained results were compared with data from a conventional rotating disk equipment, where the disk was centrically mounted. The dissolution rates at 100 rpm seemed to be on an average of 2-3 times higher for the miniaturized apparatus (RSD 0.2-56%). The preliminary studies of this prototype indicate that the miniaturized rotating disk is a promising design for the qualitative estimation of dissolution rates of substances, for example during screening in early drug discovery.