Date of Award
Reuben H. Simoyi
Antitubercular agents -- Research, Biotransformation (Metabolism) -- Research
Tuberculosis still affects a large number of the world’s population and drug resistance is becoming an increasing problem. Second line of defense antitubercular agents such as ethionamide (ETD) are thus becoming increasingly important. Since ethionamide is a prodrug, its metabolization through oxidation by a monooxygenase was successfully mimicked using peracetic acid. The reaction was found to be biphasic, with a fast initial oxidation to yield ethionamide sulfoxide (ETD-SO), which was relatively stable and was successfully isolated. We derived a bimolecular rate constant of 3.08 ± 0.72 × 102 M-1 s-1 for this initial phase of the reaction. In the slow second phase, further oxidation yielded 2-ethylisonicotinamide, where zero order kinetics were observed. Electrospray ionization mass spectroscopy (ESI-MS) was used to determine the identities of the products. No sulfinic nor sulfonic acids were detected, indicating that the sulfur-carbon bond was cleaved at the sulfenic acid stage, resulting in the release of an unstable sulfur monoxide species, which dimerized in solution to form dithionite.
Logan, Isabelle E., "Mimicking the Bioactivation of the Antitubercular Agent Ethionamide using Peracetic Acid" (2016). University Honors Theses. Paper 272.