Adenosine deaminase inhibitors: synthesis and structure-activity relationships of imidazole analogues of erythro-9-(2-hydroxy-3-nonyl)adenine.

A series of erythro-1-(2-hydroxy-3-nonyl)imidazole derivatives have been synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity, in order to introduce simplifications in the ADA inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1a) and 3-deaza-EHNA (1c). Opening the pyrimidine or pyridine ring of EHNA or 3-deaza-EHNA respectively led to compounds which are still ADA inhibitors. The most potent compound was erythro-1-(2-hydroxy-3-nonyl)imidazole-4-carboxamide (5, Ki = 3.53 x 10(-8) M), which provided potential donor and acceptor sites for hydrogen bonding. Lack of one of this sites could account for the order of potency of all compounds examined in this series. Opening the same ring in adenosine and in 3-deazaadenosine led to fully inactive compounds. These results support the hypothesis of the existence, at or near the enzyme active site, of a hydrophobic region able to bind the erythro-nonyl moiety.