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

• DOI: 10.1016/j.ejmech.2017.04.070
• Publication Date: 2017-04-27T17:48:21Z
• Authors: Michele Tonelli; Lieve Naesens; Sabrina Gazzarrini; Matteo Santucci; Elena Cichero; Bruno Tasso; Anna Moroni; Maria Paola Costi; Roberta Loddo
• Keywords: Models, Molecular; 0301 basic medicine; Microbial Sensitivity Tests; Crystallography, X-Ray; Antiviral Agents; Article; 2-dihydrotriazine derivatives; Structure-Activity Relationship; 03 medical and health sciences; Influenza A Virus, H1N1 Subtype; 6-diamino-1; Humans; 1-Aryl-4; 1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives; Anti-RSV activity; Anti-influenza A and B viruses activity; Host (human) DHFR inhibition; Anti-RSV activity; Dose-Response Relationship, Drug; Molecular Structure; Triazines; Host (human) DHFR inhibition; Respiratory Syncytial Viruses; 3. Good health; Influenza B virus; Tetrahydrofolate Dehydrogenase; Proguanil; 1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives; Anti-influenza A and B viruses activity; Anti-RSV activity; Host (human) DHFR inhibition; 1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives; Anti-influenza A and B viruses activity; Anti-RSV activity; Host (human) DHFR inhibition; Antiviral Agents; Crystallography, X-Ray; Dose-Response Relationship, Drug; Folic Acid Antagonists; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Proguanil; Respiratory Syncytial Viruses; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase; Triazines; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Folic Acid Antagonists; 1-Aryl-4,6-diamino-1,2-dihydrotriazine derivatives, Anti-influenza A and B viruses activity, Anti-RSV activity, Host (human) DHFR inhibition; Anti-influenza A and B viruses activity

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).