SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW IMIDAZOLE, PYRIMIDINE, ANDPURINE DERIVATIVES AND ANALOGS AS INHIBITORS OF XANTHINE-OXIDASE

Several derivatives of 4,5-disubstituted imidazole, 2,4,5-trisubstitut ed pyrimidine, 2-substituted purine, thiazolo[3,2-a]purine, [1,3]thiaz ino[3,2-a]purine, thiazolo[2,3-i]purine, [1,3]thiazino[2,3-i]purine, a nd 6-substituted pyrazolo[3,4-d]pyrimidine were synthesized and tested as inhibitors of the xanthine oxidase enzyme. Of those, some 4-(acyla mino)-5-carbamoylimidazoles and 2-thioalkyl-substituted purines exhibi ted very good inhibitory activity, being at least 500 times more effec tive than allopurinol. The ineffectiveness of 6-n-alkylpyrazolo[3,4-d] pyrimidines is imputable to the alkyl chain which could hinder the coo rdination with molybdenum according to the known mechanism for the bin ding of the inhibitor allopurinol; the effectiveness of imidazole deri vatives, by contrast with the ineffectiveness of 4,5-diamino-2-(thioal kyl)-6-hydroxypyrimidines, indicates the relative importance of the fi ve-membered ring in the interaction with the enzyme. Moreover, the mar ked effectiveness of the angularly-cyclized [1,3]thiazino[2,3-i]purino nes, which constitute an interesting new class of inhibitors, together with the weak activity of linearly-cyclized derivatives, allowed us t o characterize more precisely the lipophilic region of the enzyme faci ng the N(1)-C(2) positions of the substrate hypoxanthine.