2. Academic Validation
  3. Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

  • Eur J Med Chem. 2017 Jul 28:135:467-478. doi: 10.1016/j.ejmech.2017.04.070.
Michele Tonelli 1,  Lieve Naesens 2,  Sabrina Gazzarrini 3,  Matteo Santucci 4,  Elena Cichero 5,  Bruno Tasso 5,  Anna Moroni 3,  Maria Paola Costi 4,  Roberta Loddo 6
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy. Electronic address: tonelli@difar.unige.it.
  • 2 Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 3 Department of Biosciences and National Research Council (CNR), Biophysics Institute (IBF), University of Milan, Via Celoria 26, 20133 Milan, Italy.
  • 4 Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41100 Modena, Italy.
  • 5 Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
  • 6 Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
PMID: 28477572 DOI: 10.1016/j.ejmech.2017.04.070
Abstract

We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) Enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC50 = 0.060 μM), and markedly exceeded (up to 327 times) the Antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to Antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC50 ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC50 = 5.8 μM, SI > 43).

Keywords

1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives; Anti-RSV activity; Anti-influenza A and B viruses activity; Host (human) DHFR inhibition.

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