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

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.

Recent updates in click and computational chemistry for drug discovery and development

“…Copper-catalyzed 1,3-dipolar cycloaddition (CuAAC) to form 1,2,3-triazoles is the most popular reaction in click chemistry. Recently, 1,2,3-triazole backbones with hydrogen bonds, moderate dipole moments and enhanced water solubility had been widely used to generate drug candidates of anti-tumor ( Brown et al, 2022 ; Elganzory et al, 2022 ; Mohammed et al, 2022 ; Oekchuae et al, 2022 ; Oliveira et al, 2022 ; Mironov et al, 2023 ), anti-seizure ( Bhattacherjee et al, 2022 ), anti-diabetic ( Dhameja et al, 2022 ), anti-parasitic ( Aljohani et al, 2022 ), anti-bacterial ( Daher et al, 2022 ; Mokariya et al, 2022 ; Nsira et al, 2022 ) and anti-viral ( Kutkat et al, 2022 ; Tatarinov et al, 2022 ) via CuAAC click chemistry ( Figure 1A ).…”

Immune response in influenza virus infection and modulation of immune injury by viral neuraminidase

“…Improving vaccine design for identifying NA antigenic drift and novel epitopes of anti-NA antibodies [ 125 ]. Moreover, the Chinese medicinal herb and compound could inhibit the influenza virus by targeting NA [ 109 , 126 , 127 ].…”

Synthesis and biological evaluation of novel 1,2,3-triazole hybrids of cabotegravir: identification of potent antitumor activity against lung cancer

“…The incorporation of 1,2,3-triazole units into drug molecules using click chemistry approaches has gained significant popularity due to their ability to form stable compounds with hydrogen bonding interactions, enhancing drug solubility and efficacy ( Kolb and Sharpless, 2003 ). Consequently, drugs containing 1,2,3-trazole structures have been developed and reported to possess diverse biological properties, including anticancer ( Yang et al, 2020 ; Hasanpour et al, 2021 ), antimicrobial ( Lal et al, 2018 ; Addo et al, 2022 ), antiviral ( Kutkat et al, 2022 ), and anti-HIV activities ( Feng et al, 2021 ). Figure 1 illustrates examples of drugs containing 1,2,3-triazole structures with different biological activities.…”