**4. Conclusions**

Over the past 50 years, hantavirus infections have caused severe diseases with serious clinical effects on human health. Recently, this has become more evident with the emergence of new outbreaks. As mentioned, there are no FDA approved antivirals, vaccines, or immunotherapeutic agents available for the treatment of HFRS or HPS. The objective of this study was to evaluate the antiviral activity of 2-phenyl-benzotriazoles against HTNV.

All compounds were generally endowed with low cytotoxicity against cell monolayers employed in our assays to support the replication of HTNV but also against a panel of cell cultures, as reported in SM2. We identified three promising lead compounds, derivatives 2j, 2l and 2n, characterized by interesting inhibitory activity against HTNV, in vitro ten-fold more potent than the nucleoside analogue RBV, currently the only antiviral with recognized in vitro and in vivo activity. This is the first report detailing benzotriazole anti-hantavirus activity. In conclusion, the therapeutic potential of these derivatives could be considered as a good starting point for the development of second-generation effective candidates for treatment against orthohantavirus infections.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4915/12/1/122/s1, Table S1: Cytotoxicity and antiviral activity of phenyl-benzotriazoles against HTNV.

**Author Contributions:** G.S., R.L., S.P. and A.C. conceived and designed the experiments. S.P., P.C., R.I. and G.M. synthesized the compounds. G.S., B.K., S.M. and B.B. performed virus-related experiments. All authors analyzed data and contributed new reagents analytic tools. G.S., R.L., S.P., and A.C. wrote the paper. All authors reviewed and approved the manuscript.

**Funding:** This research was funded by MIUR PRIN 2015, grant number PRIN 2015C7PCYZ\_002" and Assessorato della Programmazione, Bilancio, Credito e Assetto del territorio, della Regione Autonoma della Sardegna" (Italy), Grant number Legge Regionale 7 agosto 2007: CRP1\_574". The APC was funded by PRIN 2015C7PCYZ\_002".

**Acknowledgments:** The authors are highly grateful to D. H. Krüger, Institute of Virology, Charitè University of Berlin for providing Hantaan virus strain.

**Conflicts of Interest:** The authors declare that they have no competing interests.
