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

Omnia Kutkat,Mohammed A Ramadan,Mohamed A Ali,Ahmed Kandeil,Yaseen A M M Elshaier,Wael A El-Sayed,Mohamed El Sayes,Ghazi Kayali,Mina Nabil Kamel,Richard Webby,Rabeh El-Shesheny,Yassmin Moatasim,Farouk M E Abdel-Megeid,Ahmed El Taweel,Samir T Gaballah

doi:10.3390/ph15030351

Abstract

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 (2R,3R,4S,5R)-2-((1-(Benzo[d]thiazol-2-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound 9c) had a 50% inhibitory concentration (IC50) = 2.280 µM and a ligand lipophilic efficiency (LLE) of 6.84. The compound (2R,3R,4S,5R)-2-((1-((1H-Benzo[d]imidazol-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate had IC50 = 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.

Highlights

Influenza A viruses (IAVs), including the H1N1 and H3N2 subtypes, are the major cause of seasonal influenza epidemics and occasional pandemics in humans [1]
Neuraminidase drug resistance among strains—especially N1, which has several mutations—of circulating influenza A viruses is increasing and the emergence of neuraminidase inhibitors (NAIs) resistance has become common, targeting viral neuraminidase glycoprotein (NA) is ideal because it is a surface glycoprotein, making it more accessible to drugs
Inhibitors, the use of certain structural features of available drugs could be a rapid approach towards overcoming viral resistance

Summary

Introduction

Influenza A viruses (IAVs), including the H1N1 and H3N2 subtypes, are the major cause of seasonal influenza epidemics and occasional pandemics in humans [1]. Pharmaceuticals 2022, 15, 351 subtypes of avian influenza viruses (AIVs) have emerged during the last two decades and caused human infections. Several FDA-approved antiviral drugs are commercially available to treat IAV, including neuraminidase inhibitors (NAIs) (zanamivir, peramivir, and oseltamivir phosphate) [3], M2 ion channel blockers (amantadine and rimantadine) [4], and RNA polymerase inhibitors (favipiravir and Xofluza) [5]. The continuous evolution of IAV and the overuse of antiviral drugs have led to the emergence of variant influenza strains that are resistant to amantadine, rimantadine, oseltamivir, and zanamivir, raising public health concerns and highlighting an urgent need to develop new anti-influenza drugs [6]. The design of NAIs through docking is based on the use of the conserved structure of the NA active site and on the compound fitting inside the binding site of the protein’s molecular surface [9]

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