Adenosine deaminase inhibitors: synthesis and structure-activity relationships of 2-hydroxy-3-nonyl derivatives of azoles

A series of erythro-l-(2-hydroxy-3-nonyl)azoled erivatives 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-l-(2-hydroxy-3-nonyl)-1,2,4-triazole (18e) was the most potent ADA inhibitor in the series with Ki = 0.3 rM.