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

• Main Authors: Omnia Kutkat (Author), Ahmed Kandeil (Author), Yassmin Moatasim (Author), Yaseen A. M. M. Elshaier (Author), Wael A. El-Sayed (Author), Samir T. Gaballah (Author), Ahmed El Taweel (Author), Mina Nabil Kamel (Author), Mohamed El Sayes (Author), Mohammed A. Ramadan (Author), Rabeh El-Shesheny (Author), Farouk M. E. Abdel-Megeid (Author), Richard Webby (Author), Ghazi Kayali (Author), Mohamed A. Ali (Author)
• Format: Book
• Published: MDPI AG, 2022-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph15030351; 1424-8247
• Keywords: glycosides; heterocyclic; human H1N1; antiviral; avian H5N1; neuraminidase inhibitor; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 3, p 351 (2022)

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<i>R</i>,3<i>R</i>,4<i>S</i>,5<i>R</i>)-2-((1-(Benzo[d]thiazol-2-ylmethyl)-1<i>H</i>-1,2,3-triazol-4-yl)methoxy)tetrahydro-2<i>H</i>-pyran-3,4,5-triyl triacetate (Compound <b>9c</b>) had a 50% inhibitory concentration (IC₅₀) = 2.280 µM and a ligand lipophilic efficiency (LLE) of 6.84. The compound (2<i>R</i>,3<i>R</i>,4<i>S</i>,5<i>R</i>)-2-((1-((1<i>H</i>-Benzo[d]imidazol-2-yl)methyl)-1<i>H</i>-1,2,3-triazol-4-yl)methoxy)tetrahydro-2<i>H</i>-pyran-3,4,5-triyl triacetate had IC₅₀ = 2.75 µM and LLE = 7.3 after docking analysis with the H5N1 virus neuraminidase. Compound <b>9c</b> 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.