Models for in Vivo Deiodination of 2-Iodohistidine

A variety of simple thiols fully deiodinate 2-iodohistidine within 24 h at 25°C (at pH 7.2; t1/2 = 23.5 min). Deiodination of 2,4-diiodoimidazoles occurs specifically at C-2. but at 16 therate for the 2-iodo compound, while 4-iodoimidazoles are completely stable. N-alkylation does not prevent deiodination but strong electronegative substituents at C-4 or C-5 do block the reaction. Bromoimidazoles are totally stable under the specified conditions. The proposed mechanism involves a nucleophilic attack by the soft mercaptide ion on the soft iodine in the protonated imidazole, with the imidazole ylid-carbene as the leaving group. This facile nonenzymatic delodination provides an explanation for the failure of 2-iodohistidine to maintain its strong antimalarial activity in owl monkeys beyond a 24-h period.