title: Synthesis of novel diflunisal hydrazide-hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors.
abstract: Hepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. We have previously identiﬁed the hydrazide-hydrazone scaffold as a promising hepatitis C virus (HCV) and hepatocelluler inhibitor. Herein we describe the design a number of 2',4'-difluoro-4-hydroxy-N'-(arylmethylidene) biphenyl-3-carbohydrazide (3a-t) as anti-HCV and anticancer agents. Results from evaluation of anti-HCV activity indicated that most of the synthesized hydrazone derivatives inhibited viral replication in the Huh7/Rep-Feo1b and Huh 7.5-FGR-JCI-Rluc2A reporter systems. Antiproliferative activities of increasing concentrations of 2',4'-difluoro-4-hydroxy-N'-(2-pyridyl methylidene)biphenyl-3-carbohydrazide 3b and diflunisal (2.5-40 μM) were assessed in liver cancer cell lines (Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475) with sulforhodamine B assay for 72 h. Compound 3b with 2-pyridinyl group in the hydrazone part exhibited promising cytotoxic activity against all cell lines with IC50 values of 10, 10.34 16.21 4.74, 9.29 and 8.33 μM for Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G0 phase as an indicator of apoptotic cell death induction.
authors.affiliation: Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668, İstanbul, Turkey.
authors.forename: Sevil
authors.initials: S
authors.lastname: Şenkardeş
authors.affiliation: Rutgers-New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Newark, NJ 07103, USA.
authors.forename: Neerja
authors.initials: N
authors.lastname: Kaushik-Basu
authors.affiliation: Bilkent University, Department of Molecular Biology and Genetics, 06800, Bilkent Ankara, Turkey.
authors.forename: İrem
authors.initials: İ
authors.lastname: Durmaz
authors.affiliation: Rutgers-New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Newark, NJ 07103, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Manvar
authors.affiliation: Rutgers-New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Newark, NJ 07103, USA.
authors.forename: Amartya
authors.initials: A
authors.lastname: Basu
authors.affiliation: Cancer Systems Biology Laboratory, Graduate School of Informatics Middle East Technical University, ODTU, 06800, Ankara, Turkey.
authors.forename: Rengül
authors.initials: R
authors.lastname: Atalay
authors.affiliation: Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668, İstanbul, Turkey. Electronic address: gkucukguzel@marmara.edu.tr.
authors.forename: Ş Güniz
authors.initials: ŞG
authors.lastname: Küçükgüzel
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004061:Diflunisal / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000611422:2',4'-difluoro-4-hydroxy-N'-(2-pyridylmethylidene)biphenyl-3-carbohydrazide; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D006834:Hydrazines; D006835:Hydrazones; D004061:Diflunisal
keywords: Antiviral; Diflunisal; Hepatitis C; Hepatocellular carcinom; Hydrazide–hydrazone