Abstract
Aims: The purpose of this study was to synthesis novel amine-geldanamycin hybrids (AGH) and evaluate their biological properties.
 Study Design: Experimental study.
 Place and Duration of Study: The study was carried out at the Department of Microbiology and Department of Chemistry, Faculty of Science, Silpakorn University, from December 2019 - November 2020.
 Methodology: Three new amine-geldanamycin hybrids (AGH); compounds 2 to 4 were synthesised by nucleophilic substitution of geldanamycin (1). The solubility, cytotoxicity, antiviral activity and molecular docking analyses were carried out.
 Results: The solubility of AGH in water was 1.918-5.571 mM, higher than that of compound 1. Compound 2 exhibited weak cytotoxicity activity against Vero and LLC-MK2 cells, with IC50 values of 229.19 and 330.58 µg/ml, respectively. All compounds inhibited influenza virus propagation in embryonated chicken eggs at the lowest amount of 1.25 µg per egg. They interacted positively with Hsp90, showing a binding free energy (DG) of -112.00 to -116.34 kcal/mol, which indicated lower Hsp90 affinity compared with that of geldanamycin (-133.06 kcal/mol) and 17-dimethylamino ethylamino-17-demethoxygeldanamycin (-136.55 kcal/mol), despite being bound in the similar active site. For the viral absorption, only AGH inhibited hemagglutination at a concentration of 25 µg/ml.
 Conclusion: The study findings revealed, through molecular docking analysis, that the development of AGH improved the antiviral activity. The AGH inhibited not only influenza virus propagation, but also viral absorption. Therefore, AGH could be considered a new choice for antiviral agents.
Highlights
Emerging infectious diseases of pandemic potential, such as influenza viruses, and Coronavirus, remain persistent threats to livelihoods and health around the world
The effect of GDM and amine-geldanamycin hybrids (AGH) on influenza virus propagation was evaluated at various concentrations in embryonated chicken eggs
As expected compounds 2, 3 and 4 at the lowest concentration (2 μg/ml or HAI titer of 1:50) could inhibit viral binding to the cells by HAI assay, while GDM could not inhibit viral binding to chicken red blood cells. These data suggested that GDM and AGH inhibited influenza virus propagation
Summary
Emerging infectious diseases of pandemic potential, such as influenza viruses, and Coronavirus, remain persistent threats to livelihoods and health around the world. The existing antiviral agents mainly target the key viral enzymes that are involved in the process of replication. Many viral enzyme mutations result in drug resistance. Some antiviral agents are of limited use because of their existing toxic side effects. These is a crucial need for developing new agents with novel antiviral mechanisms and broad antiviral activities. Rimantadine, amantadine [2] and neuraminidase inhibitors [3,4] have been available for prevention and therapy; adverse effects and the emergence of resistant viral strains have been reported [5,6,7]
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