Antiviral Activity of (1 S,9a R)-1-[(1,2,3-Triazol-1-yl)methyl]octahydro-1 H-quinolizines from the Alkaloid Lupinine

Abstract

Influenza is a disease of significant morbidity and mortality. The number of anti-influenza drugs is small; many of them stimulate the appearance of resistant strains. This article presents the results of assessing the antiviral activity of 1,2,3-triazole-containing derivatives of alkaloid lupinine for their ability to suppress the reproduction of orthomyxoviruses (influenza viruses: A/Vladivostok/2/09 (H1N1) and A/Almaty/8/98 (H3N2)). The ability of (1S,9aR)-1-[(1,2,3-triazol-1-yl)-methyl]octahydro-1H-quinolizines with aryl-, 4-((4-formylphenoxy)methyl)- or 4-((3-tert-butyl-5-ethyl-2-hydroxy-benzoyloxy)methyl)- substituents at the C-4 position of the triazole ring to reduce the infectivity of the virus when processing virus-containing material was established, indicating good prospects for the studied compounds as virucidal agents affecting extracellular virions. The experimental results demonstrated that the triazolyl lupinine derivatives exhibited varying degrees of affinity for both hemagglutinin and neuraminidase proteins. Furthermore, these compounds demonstrated inhibitory effects on the replication of influenza viruses with different antigenic subtypes. The obtained biological data are in agreement with the results of molecular docking, which showed strong binding energies of the investigated compounds under study with biological targets-hemagglutinin and neuraminidase proteins. Following the evaluation of antiviral efficacy among the studied triazolyl derivatives of lupinine, four compounds have been identified for subsequent comprehensive in vitro and in vivo investigations to further elucidate their antiviral properties.

Keywords: (1S,9aR)-1-[(1,2,3-triazol-1-yl)methyl]octahydro-1H-quinolizines; Tamiflu; alkaloid lupinine; antiviral activity; molecular docking; orthomyxoviruses; rimantadine.

Figure 1

Quinolizidine-type antiviral alkaloids.

Scheme 1

Synthesis of (1S,9aR)-1-[(1,2,3-triazol-1-yl)methyl]octahydro-1H-quinolizines 1–5 from (-)-lupinine 6.

Figure 2

Influence of the studied compounds on hemagglutinating activity. 1st row—A/Almaty/8/98 (H3N2); 2nd row—A/Vladivostok/2/09 (H1N1). The y-axis is the percentage of activity suppression.

Figure 3

The influence of the studied samples on neuraminidase activity. 1st row—A/Almaty/8/98 (H3N2); 2nd row—A/Vladivostok/2/09 (H1N1). The y-axis is the percentage of activity suppression.

Figure 4

The general backbone view of swine H1 hemagglutinin (PDB: 1RUY) with the docking poses of compounds 1–5 in a cavity near the vestigial esterase and receptor binding subdomains in the globular head region (Site 1) (left). The large-scale view of the superimposed docking poses with amino acid residues within 4 Å from the pose of compound 1 (right). The docked molecules are colored in blue 1, light blue 2, red 3, green 4, and magenta 5.

Figure 5

The stem region of hemagglutinin (PDB: 1RUY) shown as the dotted surface with the docking poses of compounds 1 (blue), 2 (light blue), 3 (red), 4 (green), and 5 (magenta). The poses of molecules 1–3 are overlaid within Site 2, while compounds 4 and 5 occupy Sites 3 and 4, respectively.

Figure 6

The general surface view of neuraminidase of 1918 influenza virus H1N1 with the docking poses of compounds 1–5 in the substrate-binding sites in chains A and B (PDB: 3BEQ) (left). The large-scale view of the superimposed docking poses in the site of chain B with amino acid residues within 4 Å from the pose of compound 1 (right). The docked molecules are colored in blue 1, light blue 2, red 3, green 4, and magenta 5.