title: Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-based antiviral agent.
abstract: Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Several compounds proved to be potent broad-spectrum enzyme inhibitors and significantly inhibited HIV-1 replication in vitro. Their potency depends on the substituents and the nature of the heterocyclic skeleton linked to the ethyl spacer, and structure-activity relationships are discussed in terms of the possible interaction with the RT binding site. Although the new QXPTs analogues show potent antiviral activity, none of the compounds tested overcome the pharmacokinetic disadvantages inherent to ethylpyridylthioureidic antiviral agents, which in general have very low oral bioavailability. Through an integrated effort involving synthesis, docking studies, and biological and pharmacokinetic evaluation, we investigated the structural dependence of the poor bioavailability and rapid clearance within the thioureidic series of antivirals. Replacing the ethylthioureidic moiety with a hydrazine linker led to a new antiviral lead, offering promising pharmacological and pharmacokinetic properties in terms of antiviral activity and oral bioavailability.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Facolta' di Farmacia, Universita' degli Studi di Salerno, Fisciano, Italy. campiani@unisa.it
authors.forename: G
authors.initials: G
authors.lastname: Campiani
authors.forename: F
authors.initials: F
authors.lastname: Aiello
authors.forename: M
authors.initials: M
authors.lastname: Fabbrini
authors.forename: E
authors.initials: E
authors.lastname: Morelli
authors.forename: A
authors.initials: A
authors.lastname: Ramunno
authors.forename: S
authors.initials: S
authors.lastname: Armaroli
authors.forename: V
authors.initials: V
authors.lastname: Nacci
authors.forename: A
authors.initials: A
authors.lastname: Garofalo
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.forename: G
authors.initials: G
authors.lastname: Maga
authors.forename: S
authors.initials: S
authors.lastname: Spadari
authors.forename: A
authors.initials: A
authors.lastname: Bergamini
authors.forename: L
authors.initials: L
authors.lastname: Ventura
authors.forename: B
authors.initials: B
authors.lastname: Bongiovanni
authors.forename: M
authors.initials: M
authors.lastname: Capozzi
authors.forename: F
authors.initials: F
authors.lastname: Bolacchi
authors.forename: S
authors.initials: S
authors.lastname: Marini
authors.forename: M
authors.initials: M
authors.lastname: Coletta
authors.forename: G
authors.initials: G
authors.lastname: Guiso
authors.forename: S
authors.initials: S
authors.lastname: Caccia
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D016049:Didanosine / Q000494:pharmacology; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D011725:Pyridines; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; D013890:Thiourea; D016049:Didanosine