Structure and molecular interactions of anti-thyroid drugs. Part 3.1 Methimazole: a diiodine sponge

Abstract

The anti-thyroid drug methimazole functions as a diiodine sponge. Its thione tautomer forms with diiodine a very stable electron donor–acceptor complex (K_f = 36 600 l mol^–1 in CCl₄), stabilized in a more polar medium (K_f = 92 400 l mol^–1 in CH₂Cl₂). Two stereoisomeric complexes, one planar on the non-bonding sulfur lone pair and the other perpendicular on the sulfur π electrons, are found in solution to be under steric control. The position of the charge-transfer band of many diiodine complexes of thioamides and thioureas allows the prediction of their geometry. The sulfur–iodine coordination is assisted by intramolecular hydrogen bonding NH· · ·I. This iodine amphoterism is explained by the anisotropy of its electrostatic potential surface. Hard and soft acid–base chemistry might explain the two mechanisms of action of anti-thyroid drugs, the inhibition of thyroid peroxidase via coordination to the hard heme group and the trapping of oxidized iodides via complexation of soft iodinated Lewis acids.