2. Academic Validation
  3. Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives

Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives

  • Eur J Med Chem. 2015 Nov 13:105:63-79. doi: 10.1016/j.ejmech.2015.10.002.
Irene Briguglio 1,  Roberta Loddo 2,  Erik Laurini 3,  Maurizio Fermeglia 3,  Sandra Piras 1,  Paola Corona 1,  Paolo Giunchedi 1,  Elisabetta Gavini 1,  Giuseppina Sanna 4,  Gabriele Giliberti 4,  Cristina Ibba 4,  Pamela Farci 4,  Paolo La Colla 4,  Sabrina Pricl 5,  Antonio Carta 6
Affiliations

Affiliations

  • 1 Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Muroni 23/A, 07100 Sassari, Italy.
  • 2 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.
  • 3 Molecular Simulation Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), University of Trieste, 34127 Trieste, Italy.
  • 4 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.
  • 5 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.
  • 6 Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Muroni 23/A, 07100 Sassari, Italy. Electronic address: acarta@unisss.it.
PMID: 26479028 DOI: 10.1016/j.ejmech.2015.10.002
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.

Keywords

Antiviral activity; DNA viruses; Imidazo[4,5-g]quinolines; Pyrido[2,3-g]quinoxalines; RNA viruses.

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