Synthesis of acylguanidine zanamivir derivatives as neuraminidase inhibitors and the evaluation of their bio-activities

Lin, Chien Hung; Chang, T. C.; Das, Anindya Sundar; Fang, Ming-Yu; Hung, Hui Chen; Hsu, Kai Cheng; Yang, Jinn-Moon; Itzstein, Mark von; Mong, Kwok Kong Tony; Hsu, Tsu; Lin, Chun Cheng

doi:10.1039/c3ob40624e

Cited by 32 publications

(16 citation statements)

References 29 publications

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“…Positions 4 and 6 have been replaced by larger and more complex residues generating new compounds. Yet, they remain analogous to sialic acid and so they may suffer activity losses from the appearance of mutations within the NA’s active site in viral strains after developing resistance to such sialic acid-like antiviral drugs ( Figure 5 ) [ 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

Five Novel Non-Sialic Acid-Like Scaffolds Inhibit In Vitro H1N1 and H5N2 Neuraminidase Activity of Influenza a Virus

et al. 2020

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Neuraminidase (NA) of influenza viruses enables the virus to access the cell membrane. It degrades the sialic acid contained in extracellular mucin. Later, it is responsible for releasing newly formed virions from the membrane of infected cells. Both processes become key functions within the viral cycle. Therefore, it is a therapeutic target for research of the new antiviral agents. Structure–activity relationships studies have revealed which are the important functional groups for the receptor–ligand interaction. Influenza virus type A NA activity was inhibited by five scaffolds without structural resemblance to sialic acid. Intending small organic compound repositioning along with drug repurposing, this study combined in silico simulations of ligand docking into the known binding site of NA, along with in vitro bioassays. The five proposed scaffolds are N-acetylphenylalanylmethionine, propanoic 3-[(2,5-dimethylphenyl) carbamoyl]-2-(piperazin-1-yl) acid, 3-(propylaminosulfonyl)-4-chlorobenzoic acid, ascorbic acid (vitamin C), and 4-(dipropylsulfamoyl) benzoic acid (probenecid). Their half maximal inhibitory concentration (IC50) was determined through fluorometry. An acidic reagent 2′-O-(4-methylumbelliferyl)-α-dN-acetylneuraminic acid (MUNANA) was used as substrate for viruses of human influenza H1N1 or avian influenza H5N2. Inhibition was observed in millimolar ranges in a concentration-dependent manner. The IC50 values of the five proposed scaffolds ranged from 6.4 to 73 mM. The values reflect a significant affinity difference with respect to the reference drug zanamivir (p < 0.001). Two compounds (N-acetyl dipeptide and 4-substituted benzoic acid) clearly showed competitive mechanisms, whereas ascorbic acid reflected non-competitive kinetics. The five small organic molecules constitute five different scaffolds with moderate NA affinities. They are proposed as lead compounds for developing new NA inhibitors which are not analogous to sialic acid.

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Section: Resultsmentioning

confidence: 99%

Five Novel Non-Sialic Acid-Like Scaffolds Inhibit In Vitro H1N1 and H5N2 Neuraminidase Activity of Influenza a Virus

et al. 2020

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“…Lin and co-workers have modified the guanidino group of ZA to acylguanidine derivatives [67]. Among these ZA derivatives, compound 24 bearing an S-atom and a naphthalene group turned out to be the best inhibitor against H1N1 virus with an IC 50 value of 20.1 nM comparable to that of ZA.…”

Section: Modification Of Za At C-4mentioning

confidence: 97%

From Neuraminidase Inhibitors to Conjugates: A Step Towards Better Anti-Influenza Drugs?

et al. 2014

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For the treatment of seasonal flu and possible pandemic infections the development of new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses including the resistant strains is needed. In this review, we summarize previous methods for the structural modification of zanamivir, a potent neuraminidase inhibitor that has rare drug resistance, in order to develop effective anti-influenza drugs. We also report recent research into the design of multivalent zanamivir drugs and bifunctional zanamivir conjugates, some of which have shown better efficacy in animal experiments. As a step towards developing improved antivirals, conjugating anti-influenza drugs with anti-inflammatory agents can improve oral bioavailability and also exert synergistic effect in influenza therapy.

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“…However, these results were not compared to the inhibitory activity of commercial drugs. Lin and coworkers reported the synthesis of acylguanidine zanamivir derivatives 57 (Scheme 6D) [58]. The synthetic route consisted of the reaction of different acylguanidine derivatives and amine 4 to obtain compounds 56 .…”

Section: Zanamivir Laninamivir and Other Derivativesmentioning

confidence: 99%

“…Synthesis of C-4 modified zanamivir analogues bearing triazole groups 50a – l ( A ) [55]; thiocarbamates 52a , b ( B ) [44]; alkyl chains 55a – e ( C ) [57] or acylguanidines 57 ( D ) [58]. …”

Section: Figures and Schemesmentioning

confidence: 99%

Influenza Neuraminidase Inhibitors: Synthetic Approaches, Derivatives and Biological Activity

2016

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Despite being a common viral disease, influenza has very negative consequences, causing the death of around half a million people each year. A neuraminidase located on the surface of the virus plays an important role in viral reproduction by contributing to the release of viruses from infected host cells. The treatment of influenza is mainly based on the administration of neuraminidase inhibitors. The neuraminidase inhibitors zanamivir, laninamivir, oseltamivir and peramivir have been commercialized and have been demonstrated to be potent influenza viral neuraminidase inhibitors against most influenza strains. In order to create more potent neuraminidase inhibitors and fight against the surge in resistance resulting from naturally-occurring mutations, these anti-influenza drugs have been used as templates for the development of new neuraminidase inhibitors through structure-activity relationship studies. Here, we review the synthetic routes to these commercial drugs, the modifications which have been performed on these structures and the effects of these modifications on their inhibitory activity.

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Synthesis of acylguanidine zanamivir derivatives as neuraminidase inhibitors and the evaluation of their bio-activities

Cited by 32 publications

References 29 publications

Five Novel Non-Sialic Acid-Like Scaffolds Inhibit In Vitro H1N1 and H5N2 Neuraminidase Activity of Influenza a Virus

Five Novel Non-Sialic Acid-Like Scaffolds Inhibit In Vitro H1N1 and H5N2 Neuraminidase Activity of Influenza a Virus

From Neuraminidase Inhibitors to Conjugates: A Step Towards Better Anti-Influenza Drugs?

Influenza Neuraminidase Inhibitors: Synthetic Approaches, Derivatives and Biological Activity

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