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doi:10.22028/D291-39045
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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