Synthesis and biological evaluation of new imidazole, pyrimidine, and purine derivatives and analogs as inhibitors of xanthine oxidase.
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.
Biagi
G
G
Dipartimento di Scienze Farmaceutiche, Università di Modena, Italy.
Costantini
A
A
Costantino
L
L
Giorgi
I
I
Livi
O
O
Pecorari
P
P
Rinaldi
M
M
Scartoni
V
V
D000493:Allopurinol / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011687:Purines; D011743:Pyrimidines; D000493:Allopurinol; D014969:Xanthine Oxidase