title: Novel benzidine and diaminofluorene prolinamide derivatives as potent hepatitis C virus NS5A inhibitors.
abstract: Our study describes the discovery of a series of highly potent hepatitis C virus (HCV) NS5A inhibitors based on symmetrical prolinamide derivatives of benzidine and diaminofluorene. Through modification of benzidine, l-proline, and diaminofluorene derivatives, we developed novel inhibitor structures, which allowed us to establish a library of potent HCV NS5A inhibitors. After optimizing the benzidine prolinamide backbone, we identified inhibitors embedding meta-substituted benzidine core structures that exhibited the most potent anti-HCV activities. Furthermore, through a battery of studies including hERG ligand binding assay, CYP450 binding assay, rat plasma stability test, human liver microsomal stability test, and pharmacokinetic studies, the identified compounds 24, 26, 27, 42, and 43 are found to be nontoxic, and are expected to be effective therapeutic anti-HCV agents.
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
authors.forename: Il Hak
authors.initials: IH
authors.lastname: Bae
authors.affiliation: Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
authors.forename: Youngsu
authors.initials: Y
authors.lastname: You
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
authors.forename: Chieyeon
authors.initials: C
authors.lastname: Chough
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
authors.forename: Weonu
authors.initials: W
authors.lastname: Choe
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Seon
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors.forename: Seung Gi
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea. Electronic address: sungkey@postech.ac.kr.
authors.forename: Sung Key
authors.initials: SK
authors.lastname: Jang
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea. Electronic address: kimbm@snu.ac.kr.
authors.forename: B
authors.initials: B
authors.lastname: Moon Kim
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001560:Benzidines / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011392:Proline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001560:Benzidines; D011392:Proline; D017361:Viral Nonstructural Proteins; C029876:benzidine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C056291:prolinamide
keywords: Benzidine; Diaminofluorene; HCV; NS5A inhibitor; Structure–activity relationship