Kinetics and Mechanism of Bioactivation via S-Oxygenation of Anti-Tubercular Agent Ethionamide by Peracetic Acid
† Department of Chemistry, Portland State University, Portland, Oregon 97207-0751, United States
‡ School of Chemistry and Physics, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa
J. Phys. Chem. A, 2016, 120 (41), pp 8056–8064
DOI: 10.1021/acs.jpca.6b07375
Publication Date (Web): September 29, 2016
Copyright © 2016 American Chemical Society
*E-mail address: rsimoyi@pdx.edu; phone number: 503-725-3895.
Abstract
The kinetics and mechanism of the oxidation of the important antitubercular agent, ethionamide, ETA (2-ethylthioisonicotinamide), by peracetic acid (PAA) have been studied. It is effectively a biphasic reaction with an initial rapid first phase of the reaction which is over in about 5 s and a second slower phase of the reaction which can run up to an hour. The first phase involves the addition of a single oxygen atom to ethionamide to form the S-oxide. The second phase involves further oxidation of the S-oxide to desulfurization of ETA to give 2-ethylisonicotinamide. In contrast to the stability of most organosulfur compounds, the S-oxide of ETA is relatively stable and can be isolated. In conditions of excess ETA, the stoichiometry of the reaction was strictly 1:1: CH3CO3H + Et(C5H4)C(═S)NH2 → CH3CO2H + Et(C5H4)C(═NH)SOH. In this oxidation, it was apparent that only the sulfur center was the reactive site. Though ETA was ultimately desulfurized, only the S-oxide was stable. Electrospray ionization (ESI) spectral analysis did not detect any substantial formation of the sulfinic and sulfonic acids. This suggests that cleavage of the carbon–sulfur bond occurs at the sulfenic acid stage, resulting in the formation of an unstable sulfur species that can react further to form more stable sulfur species. In this oxidation, no sulfate formation was observed. ESI spectral analysis data showed a final sulfur species in the form of a dimeric sulfur monoxide species, H3S2O2. We derived a bimolecular rate constant for the formation of the S-oxide of (3.08 ± 0.72) × 102 M–1 s–1. Oxidation of the S-oxide further to give 2-ethylisonicotinamide gave zero order kinetics.
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