SYNTHESIS AND CHARACTERIZATION OF WATER-SOLUBLE AND PHOTOLABILE 10-ARYLISOALLOXAZINES - TOOLS FOR STUDYING THE MECHANISM OF ACTION OF FLAVIN-TYPE ANTIMALARIALS

Isoalloxazine derivatives such 1a-d are promising antimalarial agents which act as inhibitors of the antioxidant enzyme glutathione reductas e and possibly of other proteins. The molecular mechanism of the pharm acological effects has not been studied in detail because compounds 1a -d are poorly soluble in aqueous solutions of physiological pH. In the present study we introduce two new types of isoalloxazine derivatives with improved solubility properties: The 10-aryl-3-carboxymethylisoal loxazines 2a-d, and the isomeric 3-methyl-10-(N-methylpyridiniumyl) is oalloxazine salts 3 and 4. In addition, for the purpose of photoaffini ty labeling experiments, the 10-aryl-8-azido-3-methylisoalloxazine 5 w as designed. The syntheses and characterizations of these new flavins as well as an alternative synthetic approach to the known antimalarial s 1a-d are described.