title: Parallel one-pot synthesis and structure-activity relationship study of symmetric formimidoester disulfides as a novel class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors.
abstract: The molecular duplication of non-nucleoside reverse transcriptase inhibitor (NNRTI) O-(2-phthalimidoethyl)-N-arylthiocarbamates (C-TCs) led to the identification of symmetric formimidoester disulfides (DSs) as a novel class of potent NNRTIs. The lead compound 1 [dimer of the isothiocarbamic form of TC O-(2-phthalimidoethyl)-N-phenylthiocarbamate] turned out to prevent the wild-type HIV-1 multiplication in MT-4 cell culture with an EC(50) value of 0.35 microM. In order to perform a structure-activity relationship (SAR) study, we prepared 40 analogues of 1 by an unprecedented one-pot method of solution-phase parallel synthesis. The SAR strategy was focused on the variation of the N-aryl portion (mono-, di- and trisubstitution of the phenyl ring and its replacement with a 1-naphthyl, cyclopropyl or benzyl group) and of the 2-phthalimidoethyl moiety (introduction of a methyl on the phthalimide substructure, replacement of the phthalimide moiety with a phenyl ring and elongation of the ethyl linker). Most DSs proved to inhibit the wild-type HIV-1 replication in cell-based assays and 15 of them were active at nanomolar concentrations. The most potent congeners (11, 15, 16, 17, 18, 19, 20 and 32, EC(50): 10-70 nM) shared the N-para-substituted phenyl moiety. Compound 17 tested in enzyme assay against recombinant wild-type reverse transcriptase displayed an IC(50) value of 0.74 microM. Compounds 19 and 33 were active at micromolar concentrations against the clinically relevant Y181C and/or K103R resistant mutants.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. sara.cesarini@unige.it
authors.forename: Sara
authors.initials: S
authors.lastname: Cesarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Spallarossa
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Laura
authors.initials: L
authors.lastname: Casula
authors.forename: Gabriella
authors.initials: G
authors.lastname: Collu
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sanna
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D009705:Nucleosides / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D004220:Disulfides; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors