In Vitro and In Vivo Antiviral Studies of New Heteroannulated 1,2,3-Triazole Glycosides Targeting the Neuraminidase of Influenza A Viruses.

There is an urgent need to develop and synthesize new anti-influenza drugs with activity against different strains, resistance to mutations, and suitability for various populations. Herein, we tested in vitro and in vivo the antiviral activity of new 1,2,3-triazole glycosides incorporating benzimidazole, benzooxazole, or benzotriazole cores synthesized by using a click approach. The Cu-catalyzation strategy consisted of 1,3-dipolar cycloaddition of the azidoalkyl derivative of the respective heterocyclic and different glycosyl acetylenes with five or six carbon sugar moieties. The antiviral activity of the synthesized glycosides against wild-type and neuraminidase inhibitor resistant strains of the avian influenza H5N1 and human influenza H1N1 viruses was high in vitro and in mice. Structure-activity relationship studies showed that varying the glycosyl moiety in the synthesized glycosides enhanced antiviral activity. The compound (2 R ,3 R ,4 S ,5 R )-2-((1-(Benzo[d]thiazol-2-ylmethyl)-1 H -1,2,3-triazol-4-yl)methoxy)tetrahydro-2 H -pyran-3,4,5-triyl triacetate (Compound 9c ) had a 50% inhibitory concentration (IC 50 ) = 2.280 µM and a ligand lipophilic efficiency (LLE) of 6.84. The compound (2 R ,3 R ,4 S ,5 R )-2-((1-((1 H -Benzo[d]imidazol-2-yl)methyl)-1 H -1,2,3-triazol-4-yl)methoxy)tetrahydro-2 H -pyran-3,4,5-triyl triacetate had IC 50 = 2.75 µM and LLE = 7.3 after docking analysis with the H5N1 virus neuraminidase. Compound 9c achieved full protection from H1N1 infection and 80% protection from H5N1 in addition to a high binding energy with neuraminidase and was safe in vitro and in vivo. This compound is suitable for further clinical studies as a new neuraminidase inhibitor.