Biagi G, Costantini A, Costantino L, Giorgi I, Livi O, Pecorari P, Rinaldi M, Scartoni V
Dipartimento di Scienze Farmaceutiche, Università di Modena, Italy.
J Med Chem. 1996 Jun 21;39(13):2529-35. doi: 10.1021/jm950876u.
Several derivatives of 4,5-disubstituted imidazole, 2,4,5-trisubstituted pyrimidine, 2-substituted purine, thiazolo[3,2-alpha]purine, [1,3]thiazino[3,2-alpha]purine, thiazolo[2,3-i]purine, [1,3]thiazino-[2,3-i]purine, and 6-substituted pyrazolo[3,4-d]pyrimidine were synthesized and tested as inhibitors of the xanthine oxidase enzyme. Of those, some 4-(acylamino)-5-carbamoylimidazoles and 2-thioalkyl-substituted purines exhibited very good inhibitory activity, being at least 500 times more effective than allopurinol. The ineffectiveness of 6-n-alkylpyrazolo[3,4-d]pyrimidines is imputable to the alkyl chain which could hinder the coordination with molybdenum according to the known mechanism for the binding of the inhibitor allopurinol; the effectiveness of imidazole derivatives, by contrast with the ineffectiveness of 4,5-diamino-2-(thioalkyl)-6-hydroxypyrimidines, indicates the relative importance of the five-membered ring in the interaction with the enzyme. Moreover, the marked effectiveness of the angularly-cyclized [1,3]thiazino[2,3-i]purinones, which constitute an interesting new class of inhibitors, together with the weak activity of linearly-cyclized derivatives, allowed us to characterize more precisely the lipophilic region of the enzyme facing the N(1)-C(2) positions of the substrate hypoxanthine.
合成了4,5-二取代咪唑、2,4,5-三取代嘧啶、2-取代嘌呤、噻唑并[3,2-α]嘌呤、[1,3]噻嗪并[3,2-α]嘌呤、噻唑并[2,3-i]嘌呤、[1,3]噻嗪并[2,3-i]嘌呤和6-取代吡唑并[3,4-d]嘧啶的几种衍生物，并测试了它们作为黄嘌呤氧化酶抑制剂的活性。其中，一些4-(酰氨基)-5-氨基甲酰基咪唑和2-硫代烷基取代的嘌呤表现出非常好的抑制活性，其效力比别嘌呤醇至少高500倍。6-正烷基吡唑并[3,4-d]嘧啶无效是由于烷基链，根据已知的抑制剂别嘌呤醇的结合机制，该烷基链可能会阻碍与钼的配位；与4,5-二氨基-2-(硫代烷基)-6-羟基嘧啶的无效性相反，咪唑衍生物的有效性表明了五元环在与酶相互作用中的相对重要性。此外，角环化的[1,3]噻嗪并[2,3-i]嘌呤酮作为一类有趣的新型抑制剂具有显著的有效性，而线性环化衍生物的活性较弱，这使我们能够更精确地表征酶面向底物次黄嘌呤的N(1)-C(2)位置的亲脂区域。
