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Titel: Redesigning of the cap conformation and symmetry of the diphenylethyne core to yield highly potent pan-genotypic NS5A inhibitors with high potency and high resistance barrier
VerfasserIn: Abdallah, Mennatallah
Hamed, Mostafa M.
Frakolaki, Efseveia
Katsamakas, Sotirios
Vassilaki, Niki
Bartenschlager, Ralf
Zoidis, Grigoris
Hirsch, Anna K. H.
Abdel-Halim, Mohammad
Abadi, Ashraf H.
Sprache: Englisch
Titel: European Journal of Medicinal Chemistry
Bandnummer: 229 (2022)
Verlag/Plattform: Elsevier
Erscheinungsjahr: 2021
Freie Schlagwörter: Hepatitis C virus
NS5A inhibitors
Pan-genotypic activity
Spatial orientation
Diphenylethyne Core
Resistance mutations
Cap conformation
DDC-Sachgruppe: 500 Naturwissenschaften
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Herein, we report the discovery of several NS5A inhibitors with potency against HCV genotype 1b in the picomolar range. Compounds (15, 33) were of extremely high potency against HCV genotype 1b (EC50 ≈ 1 pM), improved activity against genotype 3a (GT 3a) and good metabolic stability. We studied the impact of changing the cap conformation relative to the diphenylethyne core and/or compound symmetry on both potency and metabolic stability. The analogs obtained exhibited improved potency against HCV genotypes 1a, 1b, 3a and 4a compared to the clinically approved candidate daclatasvir with EC50 values in the low picomolar range and SI50s > 7 orders of magnitude. Compound 15, a symmetrically m-, m’-substituted diphenyl ethyne analog, was 150-fold more potent than daclatasvir against GT 3a, while compound 33, an asymmetrically m-, p-substituted diphenyl ethyne analog, was 35-fold more potent than daclatasvir against GT 3a. In addition, compound 15 exhibited a higher resistance barrier than daclatasvir against genotype 1b.
DOI der Erstveröffentlichung: 10.1016/j.ejmech.2021.114034
URL der Erstveröffentlichung: https://www.sciencedirect.com/science/article/abs/pii/S0223523421008837
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-390455
hdl:20.500.11880/35213
http://dx.doi.org/10.22028/D291-39045
ISSN: 0223-5234
Datum des Eintrags: 15-Feb-2023
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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