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
  • 1. Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy. Electronic address: [email protected].
  • 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.