tetano
Editor, Senior Moderator
Eur J Med Chem. 2017 Apr 27;135:467-478. doi: 10.1016/j.ejmech.2017.04.070. [Epub ahead of print]
[h=1]Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus.[/h] Tonelli M[SUP]1[/SUP], Naesens L[SUP]2[/SUP], Gazzarrini S[SUP]3[/SUP], Santucci M[SUP]4[/SUP], Cichero E[SUP]5[/SUP], Tasso B[SUP]5[/SUP], Moroni A[SUP]3[/SUP], Costi MP[SUP]4[/SUP], Loddo R[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 (EC[SUB]50[/SUB] = 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 (EC[SUB]50[/SUB] ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC[SUB]50[/SUB] = 5.8 μM, SI > 43).
Copyright ? 2017 Elsevier Masson SAS. All rights reserved.
[h=4]KEYWORDS:[/h] 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
[h=1]Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus.[/h] Tonelli M[SUP]1[/SUP], Naesens L[SUP]2[/SUP], Gazzarrini S[SUP]3[/SUP], Santucci M[SUP]4[/SUP], Cichero E[SUP]5[/SUP], Tasso B[SUP]5[/SUP], Moroni A[SUP]3[/SUP], Costi MP[SUP]4[/SUP], Loddo R[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 (EC[SUB]50[/SUB] = 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 (EC[SUB]50[/SUB] ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC[SUB]50[/SUB] = 5.8 μM, SI > 43).
Copyright ? 2017 Elsevier Masson SAS. All rights reserved.
[h=4]KEYWORDS:[/h] 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