title: Non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis and biological evaluation of novel quinoxalinylethylpyridylthioureas as potent antiviral agents.
abstract: New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyridylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopathogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inhibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, showed inhibitory activity against wild-type RT as well as against mutant RTs containing the single amino acid substitutions L1001, K103N, V106A, Y1811 and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluoropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQXPT). In cell-based assays on different cell lines and on human monocyte-macrophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a promising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral activity with zidovudine.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Facolta' di Farmacia, Universita' degli Studi di Salerno, Fisciano (Salerno), Italy. campiani@unisa.it
authors.forename: G
authors.initials: G
authors.lastname: Campiani
authors.forename: M
authors.initials: M
authors.lastname: Fabbrini
authors.forename: E
authors.initials: E
authors.lastname: Morelli
authors.forename: V
authors.initials: V
authors.lastname: Nacci
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: E
authors.initials: E
authors.lastname: Faggioli
authors.forename: I
authors.initials: I
authors.lastname: Uccella
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: C
authors.initials: C
authors.lastname: Fracasso
authors.forename: S
authors.initials: S
authors.lastname: Caccia
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009705:Nucleosides / Q000737:chemistry; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C413464:N-(2-(6-fluoro-4-oxopyrrolo(1,2-a)quinoxalin-5-yl)ethyl)-N'-(2-(5-bromopyridyl))thiourea; D009705:Nucleosides; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D013890:Thiourea