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Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors
by
Mousa, Mai H. A.
, Ahmed, Nermin S.
, Vassilaki, Niki
, Schwedtmann, Kai
, Weigand, Jan J.
, Zoidis, Grigoris
, Abadi, Ashraf H.
, Frakolaki, Efseveia
in
2,7-Diaminofluorene
/ Amino acids
/ Cytotoxicity
/ DAAs
/ HCV
/ Hepatitis C
/ Infections
/ NS5A inhibitors
/ prolinamide
/ Proteins
/ replicon assay
/ RNA polymerase
2021
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Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors
by
Mousa, Mai H. A.
, Ahmed, Nermin S.
, Vassilaki, Niki
, Schwedtmann, Kai
, Weigand, Jan J.
, Zoidis, Grigoris
, Abadi, Ashraf H.
, Frakolaki, Efseveia
in
2,7-Diaminofluorene
/ Amino acids
/ Cytotoxicity
/ DAAs
/ HCV
/ Hepatitis C
/ Infections
/ NS5A inhibitors
/ prolinamide
/ Proteins
/ replicon assay
/ RNA polymerase
2021
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Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors
by
Mousa, Mai H. A.
, Ahmed, Nermin S.
, Vassilaki, Niki
, Schwedtmann, Kai
, Weigand, Jan J.
, Zoidis, Grigoris
, Abadi, Ashraf H.
, Frakolaki, Efseveia
in
2,7-Diaminofluorene
/ Amino acids
/ Cytotoxicity
/ DAAs
/ HCV
/ Hepatitis C
/ Infections
/ NS5A inhibitors
/ prolinamide
/ Proteins
/ replicon assay
/ RNA polymerase
2021
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Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors
Journal Article
Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors
2021
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Overview
Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors; the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC50) = 36 pM and a selectivity index of >2.78 × 106). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC50 = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group.
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