Synthesis of dicationic diarylpyridines as nucleic-acid binding agents

Kumar, Arvind; Rhodes, R. A.; Spychala, Jaroslaw; Wilson, W. David; Dw, Boykin; Tidwell, R. R.; Dykstra, Christine C.; Hall, J. E.; Jones, S. K.; Schinazi, R. F.

doi:10.1016/0223-5234(96)88214-6

Cited by 36 publications

(13 citation statements)

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“…Since related compounds have been identified as protease inhibitors (14,39) and helicase inhibitors (32) and have been shown to be effective in binding to nucleic acids (24,40), multiple mechanisms of action might be employed by the nontoxic antiviral compounds reported here. Mechanisms of action of other anti-BVDV agents include inhibition of viral RNA-dependent RNA polymerase (2) and of ␣-glucosidase, which results in the misfolding of viral proteins (30).…”

Section: Discussionmentioning

confidence: 99%

“…Because of the relatedness of BVDV and HCV, research with the inhibitors of BVDV replication is useful both for the control of animal diseases and for efforts to discover drugs effective against HCV. Aromatic cationic molecules have exhibited inhibitory activity against respiratory syncytial virus (14), rotavirus (39), and human immunodeficiency virus (24). Therefore, the purpose of this research was to develop and apply a method of screening aromatic cationic molecules for in vitro toxicity and activity against BVDV.…”

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confidence: 99%

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Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

Givens

Dykstra

Brock

et al. 2003

Antimicrob Agents Chemother

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Bovine viral diarrhea virus (BVDV) is an economically significant pathogen of cattle and a problematic contaminant in the laboratory. BVDV is often used as an in vitro model for hepatitis C virus during drug discovery efforts. Aromatic dicationic molecules have exhibited inhibitory activity against several RNA viruses. Thus, the purpose of this research was to develop and apply a method for screening the aromatic cationic compounds for in vitro cytotoxicity and activity against a noncytopathic strain of BVDV. The screening method evaluated the concentration of BVDV in medium and cell lysates after 72 h of cell culture in the presence of either a 25 or 5 M concentration of the test compound. Five of 93 screened compounds were selected for further determination of inhibitory (90 and 50%) and cytotoxic (50 and 10%) concentration endpoints. The screening method identified compounds that exhibited inhibition of BVDV at nanomolar concentrations while exhibiting no cytotoxicity at 25 M concentrations. The leading compounds require further investigation to determine their mechanism of action, in vivo activity, and specific activity against hepatitis C virus.Bovine viral diarrhea virus (BVDV), which is the prototype of the Pestivirus genus of the Flaviviridae family, causes early embryonic death, abortion, teratogenesis, respiratory problems, chronic wasting syndrome, and immune system dysfunction in cattle throughout the world. Acute infections of immunocompetent cattle with different strains of BVDV have caused mortality rates of 17 to 32% (8,15,31). Vaccines have provided inconsistent protection against infection with BVDV (36).In addition to being a pathogen of cattle, BVDV can be a problematic contaminant in the laboratory. Two biotypes of BVDV (noncytopathic and cytopathic), which are based on their effects in cell cultures, are recognized (3). Noncytopathic biotypes of BVDV have been identified in commercially available lots of fetal bovine serum despite testing by the manufacturer (6, 45). Consequently, BVDV has been identified in commercially available bovine, canine, feline, and primate cell lines (16,19), human viral vaccines for measles-mumps-rubella (18, 21), and interferons for human use (20). Viral contamination of biologicals for human use may be the reason BVDV-specific antibodies have been found in some samples of human serum (17). No antiviral pharmaceuticals are currently available for controlling BVDV in the laboratory or on the farm.Hepatitis C virus (HCV), a member of the Hepacivirus genus of the family Flaviviridae, is a major cause of human liver disease throughout the world. The World Health Organization estimates that 170 million people are chronically infected with HCV (2). The organization of the HCV genome encoding the proteins for viral replication is very similar to that of BVDV (with the exception of the 5Ј-terminal protease) (4). The inability to propagate HCV efficiently by cell culture has caused researchers to adopt BVDV as a viral model for HCV (2). Because of the relatedness of BVDV...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

Givens

Dykstra

Brock

et al. 2003

Antimicrob Agents Chemother

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“…Investigations from our laboratories have focused upon diaryldiamidines as dications which exhibit both strong binding to DNA [1][2][3][4] and useful biological properties [5,6]. The precise mode of binding of these types of dicationic molcules with DNA has been found to be extremely sensitive to structure and dramatic differences in binding mode and specificity have resulted from relatively minor changes in structure [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

“…The precise mode of binding of these types of dicationic molcules with DNA has been found to be extremely sensitive to structure and dramatic differences in binding mode and specificity have resulted from relatively minor changes in structure [1][2][3][4]. The aromatic diamidines berenil and stilbamidine exhibit strong minor-groove binding at sites which have three or more consecutive AT base pairs [7,9].…”

Section: Introductionmentioning

confidence: 99%

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

Kumar

Wilson

et al. 1996

European Journal of Medicinal Chemistry

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Summary-A synthesis of 2,4-bis-(4-amidinophenyl)pyrimidine 6, 2,4-bis-[(4-imidazolin-2-yl)phenyl)]pyrimidine 7, 2,4-bis[(4-tetrahydropyrimidinyl-2-yl)phenyl]pyrimidine 8, 2,4-bis Compounds 6, 9-11, and 20 given at 5 mg/kg are more active and less toxic than pentamidine at its effective dose when evaluated against Pneumocystis carinii pneumonia (PCP) in the immunosuppressed rat model. Several compounds in this series are being evaluated further as potential new anti-PCP agents.

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“…Aromatic cationic compounds possess inhibitory action against several RNA viruses, including HIV [10], rotavirus [11] and respiratory syncytial virus [12]. Givens [13] and others used a similar novel compound, 2-(2-benzimidazolyl)-5-[4-(2-imidazolino) phenyl]furan dihydrochloride, (DB772; molecular weight =410.28) to inhibit BVDV growth in cell culture while demonstrating the compound's lack of cytotoxicity.…”

Section: Bovine Viral Diarrhoea Virus (Bvdv) Is the Prototypical Virumentioning

confidence: 99%

Antiviral Treatment of Calves Persistently Infected with Bovine Viral Diarrhoea Virus

Newcomer

Marley

Galik

et al. 2012

Antivir Chem Chemother

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Background: Animals persistently infected (PI) with bovine viral diarrhoea virus (BVDV) are a key source of viral propagation within and among herds. Currently, no specific therapy exists to treat PI animals. The purpose of this research was to initiate evaluation of the pharmacokinetic and safety data of a novel antiviral agent in BVDV-free calves and to assess the antiviral efficacy of the same agent in PI calves. Methods: One BVDV-free calf was treated with 2-(2-benzimidazolyl)-5-[4-(2-imidazolino)phenyl]furan dihydrochloride (DB772) once at a dose of 1.6 mg/kg intravenously and one BVDV-free calf was treated three times a day for 6 days at 9.5 mg/kg intravenously. Subsequently, four PI calves were treated intravenously with 12 mg/kg DB772 three times a day for 6 days and two PI control calves were treated with an equivalent volume of diluent only. Results: Prior to antiviral treatment, the virus isolated from each calf was susceptible to DB772 in vitro. The antiviral treatment effectively inhibited virus for 14 days in one calf and at least 3 days in three calves. Subsequent virus isolated from the three calves was resistant to DB772 in vitro. No adverse effects of DB772 administration were detected. Conclusions: Results demonstrate that DB772 administration is safe and exhibits antiviral properties in PI calves while facilitating the rapid development of viral resistance to this novel therapeutic agent.

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Synthesis of dicationic diarylpyridines as nucleic-acid binding agents

Cited by 36 publications

References 25 publications

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

Antiviral Treatment of Calves Persistently Infected with Bovine Viral Diarrhoea Virus

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