SYNTHESIS AND BIOLOGICAL EVALUATION OF N-6-CYCLOALKYL DERIVATIVES OF 1-DEAZAADENINE NUCLEOSIDES - A NEW CLASS OF ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS AGENTS

A series of 1-deazaadenine nucleosides with the N-6 nitrogen unsubstit uted or bearing methyl or cycloalkyl substituents, with or without a c hloro group in the 2-position, and with the glycosylic moiety being ri bose (1-16), 2'-deoxyribose (17-32), or 2',3'-dideoxyribose (33-48) we re designed and synthesized starting from 5,7-dichloro-3H-imidazo[4,5- b]pyridine (50). These compounds were evaluated for their in vitro act ivity against human immunodeficiency virus type-1 (HN-1) and herpes si mplex virus type-1 (HIV-1). In addition they were tested for their abi lity to inhibit adenosine deaminase (ADA) from calf intestine. While t he parent compounds 1-deazaadenosine (9), 2'-deoxy-1-deazaadenosine (2 5), and 2',3'-dideoxy-1-deazaadenosine (41) and the corresponding 2-ch loro derivatives were inactive, nucleosides bearing cycloalkyl substit uents on N-6 exhibited moderate to good anti-HIV-1 activity, compared to 2',3'-dideoxyadenosine, with the degree and pattern of improvement depending on the structure of the sugar moiety. In general, 2'-deoxy- and 2',3'-dideoxy derivatives were more potent compounds than the corr esponding ribose nucleosides. Compounds bearing a 6-cycloheptyl or cyc looctylamine were the most active in every series. The presence of a c hloro group in the a-position improved both activity and therapeutic i ndex in every series, the most active compound being 2'-deoxy-2-chloro -N6-cycloheptyl-1-deaza (23; ED(50) = 0.2 mu M). On the other hand, mo st of these derivatives were inactive as anti-HIV-1 agents, showing a high degree of virus selectivity. The 1-deazaadenine derivatives were not substrates of adenosine deaminase, and some of them proved to be g ood inhibitors of the enzyme. However, the ADA inhibitory activity doe s not account for the antiviral potency since increased lipophilicity and steric hindrance of substituents resulted in derivatives much less active than the parent compounds.