Modeling of the mechanism of nucleophilic aromatic substitution of fungicide chlorothalonil by glutathione |
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Authors: | Anthony C Arvanites Donald W Boerth |
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Institution: | (1) Department of Chemistry, University of Massachusetts Dartmouth, North Dartmouth, MA 02747, USA E-mail: dboerth@umassd.edu Phone: +1-508-9998244 Fax: +1-508-9999167, US |
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Abstract: | Chlorothalonil (2,4,5,6-tetrachloroisophthalonitrile, TCIN, CAS 1897-45-6) is a broad range spectrum fungicide whose fungitoxic action has been associated with the rapid formation of conjugated chlorothalonil–cellular thiol derivatives, specifically with thiol-rich enzymes such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and with glutathione (GSH). The biotransformation reaction sequence between enzyme-activated glutathione (GSH) and chlorothalonil depletes cellular glutathione reserves. The conjugation of glutathione with chlorothalonil via nucleophilic aromatic substitution was modeled for an isolated reacting species using semiempirical self-consistent field molecular orbital (SCF-MO) theory at the PM3 level. The potential energy hypersurface at each of the three possible chlorinated attack sites on chlorothalonil was elaborated using a thiolate (CH3S–) anion as a model for an enzyme-activated glutathione molecule. Calculated free energies of activation for formation of mono-RSH conjugates suggest that the order of nucleophilic attack on chlorine positions in TCIN is 2>4, 6>5 although energy differences are small (on the order of 1–2 kcal mol–1). Meisenheimer or -complexes have been isolated as true intermediates on the hypersurface for each reaction, suggesting that the mechanism follows a two-step pathway.Electronic Supplementary Material available. |
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Keywords: | Chlorothalonil Pesticide– glutathione conjugates Nucleophilic aromatic substitution Mechanism modeling |
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