Tetrahalogenated benzimidazole D-ribonucleosides are active against rat cytomegalovirus

Dittmer, Alexandra; Woskobojnik, Ina; Adfeldt, Rebekka; Drach, John C.; Townsend, Leroy B.; Voigt, Sebastian; Bogner, Elke

doi:10.1016/j.antiviral.2016.11.012

Cited by 14 publications

(7 citation statements)

References 25 publications

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“…Since there are no acidic residues corresponding to D344 of CMV in the HHV and VZM UL89 homologs, BDCRB and TCRB are unlikely to interact with HHV and VZV. This accords with in vitro results showing that benzimidazole ribonucleosides have little to no effect against HHV, VZV, HHV-6, and HHV-8 [30]. Along with the specific nature of these compounds, they also are metabolized too rapidly in vivo, despite their effectiveness in cell culture [36,37].…”

Section: Introductionsupporting

confidence: 77%

“…Inhibiting the viral terminase or other components of the viral DNA packaging motor is expected to be more effective and has less target-related toxicity than nucleoside analogs. This is due to the fact that the molecular functions of the DNA packaging motor, capsid formation, DNA cleavage, and packaging of DNA into capsids, are virus-specific and not found in mammalian cells [30,31]. Current CMV terminase inhibitors include benzimidazoles and the 3,4-dihydro-quinazoline-4-yl-acetic acid derivative, letermovir [32].…”

Section: Introductionmentioning

confidence: 99%

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Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs

et al. 2019

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Approximately 80% of adults are infected with a member of the herpesviridae family. Herpesviruses establish life-long latent infections within neurons, which may reactivate into lytic infections due to stress or immune suppression. There are nine human herpesviruses (HHV) posing health concerns from benign conditions to life threatening encephalitis, including cancers associated with viral infections. The current treatment options for most HHV conditions mainly include several nucleoside and nucleotide analogs targeting viral DNA polymerase. Although these drugs help manage infections, their common mechanism of action may lead to the development of drug resistance, which is particularly devastating in immunocompromised patients. Therefore, new classes of drugs directed against novel targets in HHVs are necessary to alleviate this issue. We analyzed the conservation rates of all proteins in herpes simplex virus 1 (HHV-1), a representative of the HHV family and one of the most common viruses infecting the human population. Furthermore, we generated a full-length structure model of the most conserved HHV-1 protein, the DNA packaging terminase pUL15. A series of computational analyses were performed on the model to identify ATP and DNA binding sites and characterize the dynamics of the protein. Our study indicates that proteins involved in HHV-1 DNA packaging and cleavage are amongst the most conserved gene products of HHVs. Since the packaging protein pUL15 is the most conserved among all HHV-1 gene products, the virus will have a lower chance of developing resistance to small molecules targeting pUL15. A subsequent analysis of the structure of pUL15 revealed distinct ATP and DNA binding domains and the elastic network model identifies a functionally important hinge region between the two domains of pUL15. The atomic information on the active and allosteric sites in the ATP- and DNA-bound model of pUL15 presented in this study can inform the structure-based drug discovery of a new class of drugs to treat a wide range of HHVs.

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Section: Introductionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs

et al. 2019

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“…Chemotherapy is the main cancer treatment strategy while patients administered the available chemotherapeutics are suffering undesirable side effects [2] hence, new research studies are stressed by scientists in order to discover new anticancer promising agents. Because of the structure similarity to the naturally occurring purines, some benzimidazole derivatives have proved biological importance; [3] such as: anticancer [4][5][6] (Figure 1), antimicrobial [7][8][9][10], antifungal [11][12][13][14][15], antiviral [18][19][20], anthelmintic [21][22], antihypertensive [23][24][25][26][27], antitubercular [28][29][30][31], antiulcer activity [32], antihistaminic [33] and anti-oxidant [34][35][36]. Imine group (-C=N-) included in hydrazones is considered an essential moiety of fictional group plays essential role in biological system such as mechanism of transformation reaction and racemization ( Figure 2) [37].…”

Section: Introductionmentioning

confidence: 99%

Novel Benzimidazole/Hydrazone Derivatives as Promising Anticancer Lead Compounds: Design, Synthesis, and Molecular Docking Study

Morcoss

Abdelhafez

Abdel‐Rahman

et al. 2020

Journal of advanced Biomedical and Pharmaceutical Sciences

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A novel series of benzimidazole-hydrazone derivatives was designed and synthesized as a potential anti-cancer agents. The structure of the target compounds was assured using different spectroscopic methods such as IR, 1 H NMR, 13 C NMR and elemental analysis. These new compounds were examined and evaluated for their antiproliferative activities against 60 different cell lines. Combination of benzimidazole scaffold with hydrazone group exhibited promising anti-cancer activity. Compounds 3a and 3b showed significant activity against different cancer cells lines between 50-84 % of growth inhibition. A molecular modeling study for compounds 3a and 3b into VEGFR-2 active site was performed with reasonable docking scores.

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“…[4,5] In this view, the incorporation of benzoyl group into benzimidazole can enhance their lipophilicity, bioavailability, and thereby increase the biological potency. [6] Benzimidazole derivatives comprise a auspicious group of heterocyclic derivatives having a large number of pharmaceutical activities such as antimicrobial, [7][8][9][10] antiprotozoal, [11] anthelmintic, [12][13][14] anticancer, [15][16][17] anti-HIV, [18] anticonvulsant, [19] anti-inflammatory, [20] antineoplastic, [21] antiulcer, [22] antiviral, [23][24][25] antihypertensive, [26,27] antitubercular, [28,29] antiulcer activity, [30] anti-histaminic [31] and anti-oxidant. [32,33] In the literature survey, 5,6-dinitro and 2-trifluoromethyl substituted benzimidazole derivatives displayed excellent antimicrobial activity.…”

Section: Introductionmentioning

confidence: 99%

Microwave assisted synthesis, biological activities, and in silico investigation of some benzimidazole derivatives

Bhavsar

Acharya

Jethava

et al. 2020

Journal of Heterocyclic Chem

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Some derivatives of 2-substituted benzimidazole were prepared via coupling of N-methyl-o-phenylenediamine or o-phenylenediamine with different aromatic aldehydes catalyzed by Ni(OAc) 2 in the presence of chloroform under microwave-assisted conditions. Structural confirmation of all synthesized molecules was investigated by FT-IR, 13 C NMR, 1 H NMR, ESI-MS, and Elemental analysis. All prepared molecules were examined for in-vitro pharmaceutical activities like antibacterial, antifungal, antimalarial, antituberculosis, and antioxidant. Additionally, in silico study was also carried out. We also evaluated the steadiness and molecular interaction of docked complex, that is, complex of molecule (7s) with PDB: 5ZNI and complex of derivative (7l) with PDB: 3VLN, we have established a molecular dynamics model on the best dock molecules. All newly prepared molecules were authenticated to have excellent pharmacokinetics stuffs via calculated ADME-Tox descriptors, which signifying that these derivatives could be utilized as hit for the expansion of the some innovative active compounds.

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Tetrahalogenated benzimidazole D-ribonucleosides are active against rat cytomegalovirus

Cited by 14 publications

References 25 publications

Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs

Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs

Novel Benzimidazole/Hydrazone Derivatives as Promising Anticancer Lead Compounds: Design, Synthesis, and Molecular Docking Study

Microwave assisted synthesis, biological activities, and in silico investigation of some benzimidazole derivatives

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