Inhibition of 5-Lipoxygenase by Substituted 3,4-Dihydro-2H-1,4-thiazines

A series of substituted 3,4-dihydro-2H-1,4-thiazines inhibit 5-lipoxygenase from rat leukocytes and exhibit submicromolar IC50 values. A novel synthesis of these compounds was developed based on the formation of hydroxymethyleneamine 13 and its cyclization to the title compounds. The dihydrothiazines have low oxidation potentials, typically E1/2 is near 0.3 V, and a representative compound reduces Fe(III)(phen)3, with k = 105 M−1s−1. We propose that these lipophilic compounds bind to 5-lipoxygenase and reduce the iron in the active site, thus inactivating the enzyme.