tetano
Editor, Senior Moderator
Pharmaceuticals (Basel)
. 2022 Mar 14;15(3):351.
doi: 10.3390/ph15030351.
In Vitro and In Vivo Antiviral Studies of New Heteroannulated 1,2,3-Triazole Glycosides Targeting the Neuraminidase of Influenza A Viruses
Omnia Kutkat[SUP] 1 [/SUP], Ahmed Kandeil[SUP] 1 2 [/SUP], Yassmin Moatasim[SUP] 1 [/SUP], Yaseen A M M Elshaier[SUP] 3 [/SUP], Wael A El-Sayed[SUP] 4 5 [/SUP], Samir T Gaballah[SUP] 4 [/SUP], Ahmed El Taweel[SUP] 1 [/SUP], Mina Nabil Kamel[SUP] 1 [/SUP], Mohamed El Sayes[SUP] 1 [/SUP], Mohammed A Ramadan[SUP] 6 [/SUP], Rabeh El-Shesheny[SUP] 1 [/SUP], Farouk M E Abdel-Megeid[SUP] 4 [/SUP], Richard Webby[SUP] 2 [/SUP], Ghazi Kayali[SUP] 7 [/SUP], Mohamed A Ali[SUP] 1 [/SUP]
Affiliations
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 (IC[SUB]50[/SUB]) = 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 IC[SUB]50[/SUB] = 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.
Keywords: antiviral; avian H5N1; glycosides; heterocyclic; human H1N1; neuraminidase inhibitor.
. 2022 Mar 14;15(3):351.
doi: 10.3390/ph15030351.
In Vitro and In Vivo Antiviral Studies of New Heteroannulated 1,2,3-Triazole Glycosides Targeting the Neuraminidase of Influenza A Viruses
Omnia Kutkat[SUP] 1 [/SUP], Ahmed Kandeil[SUP] 1 2 [/SUP], Yassmin Moatasim[SUP] 1 [/SUP], Yaseen A M M Elshaier[SUP] 3 [/SUP], Wael A El-Sayed[SUP] 4 5 [/SUP], Samir T Gaballah[SUP] 4 [/SUP], Ahmed El Taweel[SUP] 1 [/SUP], Mina Nabil Kamel[SUP] 1 [/SUP], Mohamed El Sayes[SUP] 1 [/SUP], Mohammed A Ramadan[SUP] 6 [/SUP], Rabeh El-Shesheny[SUP] 1 [/SUP], Farouk M E Abdel-Megeid[SUP] 4 [/SUP], Richard Webby[SUP] 2 [/SUP], Ghazi Kayali[SUP] 7 [/SUP], Mohamed A Ali[SUP] 1 [/SUP]
Affiliations
- PMID: 35337148
- PMCID: PMC8950700
- 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 (IC[SUB]50[/SUB]) = 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 IC[SUB]50[/SUB] = 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.
Keywords: antiviral; avian H5N1; glycosides; heterocyclic; human H1N1; neuraminidase inhibitor.