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Titel: Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors
VerfasserIn: Hamdy, Jehad
Emadeldin, Nouran
Hamed, Mostafa M.
Frakolaki, Efseveia
Katsamakas, Sotirios
Vassilaki, Niki
Zoidis, Grigoris
Hirsch, Anna K. H.
Abdel-Halim, Mohammad
Abadi, Ashraf H.
Sprache: Englisch
Titel: Pharmaceuticals
Bandnummer: 15
Heft: 5
Verlag/Plattform: MDPI
Erscheinungsjahr: 2022
Freie Schlagwörter: direct-acting antivirals
NS5A inhibitors
HCV antivirals
pan-genotypic activity
Gt1b molecular docking
diphenyldiyne core
DDC-Sachgruppe: 500 Naturwissenschaften
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)- approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-metapositioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC50 value in the picomolar range, and showed high genotypic coverage with nanomolar range EC50 values against four more genotypes. This together with its high metabolic stability (t1 ⁄2 > 120 min) makes it a potential preclinical candidate.
DOI der Erstveröffentlichung: 10.3390/ph15050632
URL der Erstveröffentlichung: https://www.mdpi.com/1424-8247/15/5/632
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-390491
hdl:20.500.11880/35217
http://dx.doi.org/10.22028/D291-39049
ISSN: 1424-8247
Datum des Eintrags: 16-Feb-2023
Bezeichnung des in Beziehung stehenden Objekts: Supplementary Materials
In Beziehung stehendes Objekt: https://www.mdpi.com/article/10.3390/ph15050632/s1
Fakultät: NT - Naturwissenschaftlich- Technische Fakultät
Fachrichtung: NT - Pharmazie
Professur: NT - Prof. Dr. Anna Hirsch
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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