Adenosine deaminase inhibitors: synthesis and structure-activity relationships of 2-hydroxy-3-nonyl derivatives of azoles.
A series of erythro-1-(2-hydroxy-3-nonyl)azole derivatives have been synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity, in order to introduce simplifications in the ADA inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1a). The synthesis of most of the reported compounds was achieved by reaction of 2-bromo-3-nonanone with the suitable azole followed by reduction of the carbonyl group to give a diastereoisomeric mixture of N-substituted (2-hydroxy-3-nonyl)azoles. Separation of diastereoisomers was achieved by HPLC or by preparative TLC plates. The results of the enzymatic test indicate that the nitrogen in the 3-position, and secondly, the nitrogen in the 5-position are very important for the interaction of the azole ring with the inhibitory site on the enzyme. In fact, the pyrazole and the 2-substituted 1,2,3-triazole derivatives (10 and 15, respectively) are nearly inactive, whereas the erythro-1-(2- hydroxy-3-nonyl)-1,2,4-triazole (18e) was the most potent ADA inhibitor in the series with Ki = 0.3 microM.
Cristalli
G
G
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
Eleuteri
A
A
Volpini
R
R
Vittori
S
S
Camaioni
E
E
Lupidi
G
G
D058892:Adenosine Deaminase Inhibitors; D001393:Azoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D001393:Azoles; D014230:Triazoles; C085411:1-(2-hydroxy-3-nonyl)-1,2,4-triazole