Τίτλος:
Design and synthesis of novel symmetric fluorene-2,7-diamine derivatives as potent hepatitis C virus inhibitors
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2021 by the authors.
Συγγραφείς:
Mousa, M.H.A.
Ahmed, N.S.
Schwedtmann, K.
Frakolaki, E.
Vassilaki, N.
Zoidis, G.
Weigand, J.J.
Abadi, A.H.
Λέξεις-κλειδιά:
adenosine triphosphate; daclatasvir; diamine derivative; fluorene 2,7 diamine derivative; isoleucine; nonstructural protein 5A inhibitor; phenylglycine; prolinamide; unclassified drug, antiviral activity; Article; chemical modification; controlled study; cytotoxicity assay; drug design; drug selectivity; drug structure; drug synthesis; EC50; gel electrophoresis; Hepatitis C virus subtype 1b; high performance liquid chromatography; human; human cell; luciferase assay; mass spectrometry; nonhuman; RNA extraction; structure activity relation; Western blotting
