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Eur J Med Chem. 2017 Apr 27;135:467-478. doi: 10.1016/j.ejmech.2017.04.070. [Epub ahead of print]
Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus.
Tonelli M1, Naesens L2, Gazzarrini S3, Santucci M4, Cichero E5, Tasso B5, Moroni A3, Costi MP4, Loddo R6.
Author information
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).
Copyright ? 2017 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives; Anti-RSV activity; Anti-influenza A and B viruses activity; Host (human) DHFR inhibition
PMID: 28477572 DOI: 10.1016/j.ejmech.2017.04.070
Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus.
Tonelli M1, Naesens L2, Gazzarrini S3, Santucci M4, Cichero E5, Tasso B5, Moroni A3, Costi MP4, Loddo R6.
Author information
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).
Copyright ? 2017 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives; Anti-RSV activity; Anti-influenza A and B viruses activity; Host (human) DHFR inhibition
PMID: 28477572 DOI: 10.1016/j.ejmech.2017.04.070