Effect of structure on phenothiazine cation radical reactions in aqueous buffers

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Abstract
The reactions of the cation radicals of 11 phenothiazine tranquilizers were examined in mildly acidic aqueous buffers. Of the 11, those having an aminopropyl side chain in the 10 position reacted to form 0.5 mol of sulfoxide and 0.5 mol of parent drug/mol of initial radical. Cation radicals with different side chains react to form additional products, which remain to be identified but probably result from hydroxylation of the phenothiazine ring. The decay kinetics of 3 of the cation radicals undergoing reactions with known stoichiometry (chlorpromazine, promazine and triflupromazine) were studied in detail, and apparently they all react via the same mechanism. The mechanism involves attack of the cation radical by a nucleophile, and radicals with electron-withdrawing groups in the 2 position react more quickly. Since the cation radicals with faster reaction rates with nucleophiles are more pharmacologically active, the cation radical-nucleophile interaction may be responsible for binding of phenothiazines to receptor proteins.

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