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  • The first example of a broadly acting antiviral drug is


    The first example of a broadly-acting antiviral drug is ribavirin, a nucleoside analogue that was proposed to act directly at the level of the viral polymerase, although an indirect effect via inhibition of the host-cell IMP dehydrogenase and depletion of the GTP pool seems more plausible [9]. Another enzyme of the purine and pyrimidine pathways is dihydrofolate reductase (DHFR) which catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), a crucial cofactor for the biosynthesis of IMP and thymidylate. Folate antagonists interfering with DHFR can be applied in diverse pharmacological (i.e. antimalarial, antibacterial and antineoplastic) settings [10], [11], [12], [13]. The licensed antifolates trimethoprim [14], pyrimethamine [15] and cycloguanil are potent inhibitors of bacterial and protozoal DHFR, respectively, but only weak inhibitors of mammalian DHFR enzymes. On the other hand, the drug methotrexate (MTX) is a potent unselective DHFRs inhibitor (Ki = 0.01–0.2 nM) [16], because of its close structural similarity with dihydrofolic acid, the natural substrate of the enzyme [17]. MTX shows a binding affinity to human DHFR (hDHFR) 1000-fold higher than that of folic N6-methyladenosine synthesis [16], explaining its clinical application as anticancer, anti-inflammatory and immunosuppressive agent. Indeed, the MTX capability of affecting different intracellular pathways has been very recently described, highlighting a rather complex mechanism of action besides the most important therapeutic activity related to hDHFR inhibition [18]. Ongoing research efforts to develop novel antifolates for cancer chemotherapy and microbial infections continue to be extensively reviewed [19]. Cycloguanil is the active metabolite of the antimalarial drug proguanil (Paludrine® or Malarone®), that is approved for prophylaxis and treatment of infections by Plasmodium vivax or falciparum. The species-selective activity of cycloguanil (and pyrimethamine) has traditionally been attributed to higher affinity of the drug for Plasmodium bifunctional dihydrofolate reductase-thymidylate synthetase (DHFR-TS) than for hDHFR [20]. Since 1991, cycloguanil and related 1-aryl-4,6-diamino-1,2-dihydrotriazines were studied with the aim at treating Pneumocystis Carinii pneumonia [21], searching for more selective inhibitors for P. Carinii DHFR over host DHFR (especially human enzyme). Indeed, trimethoprim, the antifolate most widely used for that kind of infection, was a poor inhibitor of P. Carinii DHFR (Ki = 280 μM) and showed about 6-fold greater selectivity for hDHFR (Ki = 48 μM). Some 1-aryl-4,6-diamino-1,2-dihydrotriazines exhibited a selective P. Carinii DHFR inhibition, while cycloguanil and some related analogues (two of them corresponding to our compounds 11 and 14) were disclosed to bind slightly stronger to hDHFR (cycloguanil, Ki = 43.0 μM) than to P. Carinii enzyme (cycloguanil, Ki = 109.0 μM). Finally, the Author suggested that not only the expected selective fungal enzyme inhibitors, but even compounds with higher species-selectivity profile for hDHFR showed improvement over agents currently used to treat P. Carinii infections. In our previous studies, we focused on the design of antiviral agents by exploring diverse and original chemotypes [22], [23], [24], [25], [26]. In the search of novel promising derivatives, in vessel elements manuscript we reported for the first time the intriguing antiviral profile of cycloguanil (1). Based on this information, we deemed interesting to proceed our work directed to the design, synthesis and evaluation of the antiviral activity and cytotoxicity played by further compounds, against a wide range of RNA and DNA viruses. In particular, we explored the most relevant structure-activity relationship (SAR) exhibited within a series of structural analogues of cycloguanil (1), including a number of 1-aryl-4,6-diamino-1,2-dihydrotriazines.
    Results and discussion
    Biological evaluation
    Molecular modelling studies