title: Synthesis and biological evaluation of N6-cycloalkyl derivatives of 1-deazaadenine nucleosides: a new class of anti-human immunodeficiency virus agents.
abstract: A series of 1-deazaadenine nucleosides with the N6 nitrogen unsubstituted or bearing methyl or cycloalkyl substituents, with or without a chloro group in the 2-position, and with the glycosylic moiety being ribose (1-16), 2'-deoxyribose (17-32), or 2', 3'-dideoxyribose (33-48) were designed and synthesized starting from 5,7-dichloro-3H-imidazo[4,5-b] pyridine (50). These compounds were evaluated for their in vitro activity against human immunodeficiency virus type-1 (HIV-1) and herpes simplex virus type-1 (HSV-1). In addition they were tested for their ability to inhibit adenosine deaminase (ADA) from calf intestine. While the parent compounds 1-deazaadenosine (9), 2'-deoxy-1-deazaadenosine (25), and 2',3'-dideoxy-1- deazaadenosine (41) and the corresponding 2-chloro derivatives were inactive, nucleosides bearing cycloalkyl substituents on N6 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 corresponding ribose nucleosides. Compounds bearing a 6-cycloheptyl or cyclooctylamine were the most active in every series. The presence of a chloro group in the 2-position improved both activity and therapeutic index in every series, the most active compound being 2'-deoxy-2-chloro-N6-cycloheptyl-1-deazaadenosine (23; ED50 = 0.2 microM). On the other hand, most of these derivatives were inactive as anti-HSV-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 good inhibitors of the enzyme. However, the ADA inhibitory activity does not account for the antiviral potency since increased lipophilicity and steric hindrance of substituents resulted in derivatives much less active than the parent compounds.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cristalli
authors.forename: S
authors.initials: S
authors.lastname: Vittori
authors.forename: A
authors.initials: A
authors.lastname: Eleuteri
authors.forename: R
authors.initials: R
authors.lastname: Volpini
authors.forename: E
authors.initials: E
authors.lastname: Camaioni
authors.forename: G
authors.initials: G
authors.lastname: Lupidi
authors.forename: N
authors.initials: N
authors.lastname: Mahmood
authors.forename: F
authors.initials: F
authors.lastname: Bevilacqua
authors.forename: G
authors.initials: G
authors.lastname: Palù
mesh_terms: D000241:Adenosine / Q000138:chemical synthesis* / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D015497:HIV-1 / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D058892:Adenosine Deaminase Inhibitors; D000998:Antiviral Agents; D000241:Adenosine