Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

Autor: Viktor Kelemen, Lieve Naesens, Son Le Thai, Pál Herczegh, Annelies Stevaert, Evelien Vanderlinden, Gyula Batta, Magdolna Csávás, Anikó Borbás, Zsolt Szűcs, Erzsébet Rőth
Rok vydání: 2018
Předmět:
Maleimide
0301 basic medicine
SI
selectivity index
chemistry.chemical_compound
Drug Discovery
MCC
minimum cytotoxic concentration
logP
logarithm of the partition coefficient
Influenza virus inhibitor
Molecular Structure
Galp
galactopyranose
Chemistry
Teicoplanin
General Medicine
NA
neuraminidase
Glycopeptide
DCM
dichloromethane
HIV
human immunodeficiency virus
CPE
cytopathic effect
Influenza A virus
Lipophilicity
Click chemistry
DMF
dimethylformamide
tosyl
p-toluenesulfonyl
medicine.drug
Cell Survival
Stereochemistry
medicine.drug_class
SARS-CoV
severe acute respiratory syndrome coronavirus
030106 microbiology
Et3N
triethylamine
MTS
3-(4
5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
Microbial Sensitivity Tests
Glycopeptide antibiotic
Sulfonamide
SEM
standard error of the mean
Antiviral Agents
Article
Cell Line
Structure-Activity Relationship
03 medical and health sciences
medicine
Humans
Structure–activity relationship
Cell Proliferation
Pharmacology
TLC
thin layer chromatography
Dose-Response Relationship
Drug
Lipoglycopeptide
Organic Chemistry
PMB
p-methoxybenzyl
Coronavirus
Influenza B virus
M2
Matrix-2
030104 developmental biology
TEG
tetraethylene glycol
Ph
phenyl
MDCK
Madin−Darby Canine Kidney
Linker
HA
hemagglutinin
Zdroj: European Journal of Medicinal Chemistry
ISSN: 0223-5234
Popis: Six series of semisynthetic lipophilic glycopeptide antibiotic derivatives were evaluated for in vitro activity against influenza A and B viruses. The new teicoplanin pseudoaglycon-derived lipoglycopeptides were prepared by coupling one or two side chains to the N-terminus of the glycopeptide core, using various conjugation methods. Three series of derivatives bearing two lipophilic groups were synthesized by attaching bis-alkylthio maleimides directly or through linkers of different lengths to the glycopeptide. Access to the fourth and fifth series of compounds was achieved by click chemistry, introducing single alkyl/aryl chains directly or through a tetraethylene glycol linker to the same position. A sixth group of semisynthetic derivatives was obtained by sulfonylation of the N-terminus. Of the 42 lipophilic teicoplanin pseudoaglycon derivatives tested, about half showed broad activity against influenza A and B viruses, with some of them having reasonable or no cytotoxicity. Minor differences in the side chain length as well as lipophilicity appeared to have significant impact on antiviral activity and cytotoxicity. Several lipoglycopeptides were also found to be active against human coronavirus.
Graphical abstract Image 1
Highlights • Multiple series of lipophilic teicoplanin pseudoaglycon derivatives were prepared. • Alkyl or aryl chains were coupled to the N-terminus by various conjugation methods. • The activity of new antibiotic derivatives was evaluated against influenza viruses. • Half of the 42 derivatives showed high activity against influenza A and B viruses. • The length and lipophilicity of the side chains influence the antiviral activity.
Databáze: OpenAIRE
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