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Purine analogues as potential CDK9 inhibitors: New pyrazolopyrimidines as anti-avian influenza virus.
Khedr, Mohammed A; Zaghary, Wafaa A; Elsherif, Gihad E; Azzam, Rasha A; Elgemeie, Galal H.
Afiliación
  • Khedr MA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
  • Zaghary WA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
  • Elsherif GE; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
  • Azzam RA; Department of Chemistry, Faculty of Science, Helwan University, Cairo, Egypt.
  • Elgemeie GH; Department of Chemistry, Faculty of Science, Helwan University, Cairo, Egypt.
Nucleosides Nucleotides Nucleic Acids ; 41(7): 643-670, 2022.
Article en En | MEDLINE | ID: mdl-35400296
Cyclin dependent kinases (CDKs) are a group of enzymes involved in different phases of the cell cycle. In addition, it has been reported that CDK9 could be used as a crucial target for the development of antiviral drugs such as purine analogues; roscovitine and dinaciclib. A new series of benzothiazolyl pyrazolopyrimidine carboxamide derivatives were synthesized and evaluated for their antiviral activity against avian influenza "bird flu" (H5N1). The novel compounds were synthesized via the reaction of pyrazolo carboxamide derivatives with different derivatives of ylidine benzothiazole. The reaction proceeded via a Michael addition pathway. Antiviral activity was determined using a plaque reduction assay against the H5N1 virus. Five compounds showed the highest inhibitory activity in the range of 61.6 to 71.6% at 0.1 µmol/mL. Based on a molecular docking study, an enzyme assay was carried out against CDK9 for the previously mentioned top-ranked compounds. It was found that compound 11f was the most potent inhibitor of CDK9 with an IC50 of 0.062 µmol/mL. A QSAR model was built to determine the hidden feature responsible for the biological activity of the novel compounds. It was found that two sets of descriptors, 3 D Potential energy descriptors and 2 D Atom Counts and Bond Counts descriptors, were correlated to a linear model with RMSE and r2 coefficient values of 0.75 and 0.80, respectively. A molecular dynamic simulations study of 11f over 10 ns against dinaciclib showed that both 11f and dinaciclib achieved equilibrium at 2 Å.Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2022.2059674 .
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Subtipo H5N1 del Virus de la Influenza A Idioma: En Revista: Nucleosides Nucleotides Nucleic Acids Asunto de la revista: BIOQUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Subtipo H5N1 del Virus de la Influenza A Idioma: En Revista: Nucleosides Nucleotides Nucleic Acids Asunto de la revista: BIOQUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Estados Unidos