title: Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives.
abstract: Linear aromatic N-tricyclic compounds with promising antiviral activity and minimal cytotoxicity were prepared and analyzed in the last years. Specifically, the pyrido[2,3-g]quinoxalinone nucleus was found endowed with high potency against several pathogenic RNA viruses as etiological agents of important veterinary and human pathologies. Following our research program on new antiviral agents we have designed, synthesized and assayed new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. Lead compounds 1-4 were further modified to enhance their antiviral activity and reduce their cytotoxicity. Thus, different substituents were introduced on N atom at position 1 or the O atom at position 2 of the leads; contextually, several groups were inserted on the nitrogen atom at position 7 of diaminoquinoline intermediates. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA virus families containing single-stranded (either positive-sense (ssRNA+) or negative-sense (ssRNA-)), and double-stranded genomes (dsRNA), and against two representatives of DNA virus families. Some derivatives emerged as potential leads for further development as antiviral agents against some viruses of public health significance, such as RSV, Reo, BVDV and HCV. Particularly, compounds 4, 11b, 11c, 13c, 15a, 18 and 21 resulted active against BVDV at concentrations ranging from 1.3 to 5 μM. Compound 21 was also evaluated for its activity on the BVDV RdRp. Compound 4 was also tested as potential anti-HCV compound in a subgenomic replication assay. Molecular simulation results provided a molecular rationale for the anti-BVDV activity of these compounds.
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Briguglio
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università degli Studi di Cagliari, Cittadella Universitaria s.p.8, Km 0,700, 09042 Monserrato (Ca), Italy. Electronic address: rloddo@unica.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste, 34127 Trieste, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Piras
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Corona
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giunchedi
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gavini
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università degli Studi di Cagliari, Cittadella Universitaria s.p.8, Km 0,700, 09042 Monserrato (Ca), Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sanna
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università degli Studi di Cagliari, Cittadella Universitaria s.p.8, Km 0,700, 09042 Monserrato (Ca), Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Giliberti
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università degli Studi di Cagliari, Cittadella Universitaria s.p.8, Km 0,700, 09042 Monserrato (Ca), Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ibba
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università degli Studi di Cagliari, Cittadella Universitaria s.p.8, Km 0,700, 09042 Monserrato (Ca), Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Farci
authors.affiliation: Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università degli Studi di Cagliari, Cittadella Universitaria s.p.8, Km 0,700, 09042 Monserrato (Ca), Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste, 34127 Trieste, Italy; National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, 34127 Trieste, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Muroni 23/A, 07100 Sassari, Italy. Electronic address: acarta@unisss.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Carta
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004267:DNA Viruses / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012328:RNA Viruses / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; D011725:Pyridines; D011804:Quinolines; D011810:Quinoxalines; C000609947:imidazo(4,5-g)quinoline; C000609948:pyrido(2,3-g)quinoxalinone
keywords: Antiviral activity; DNA viruses; Imidazo[4,5-g]quinolines; Pyrido[2,3-g]quinoxalines; RNA viruses