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Synthesis, Molecular Modelling and Biological Studies of 3-Hydroxy-Pyrane-4-One and 3-Hydroxy-Pyridine-4-One Derivatives As Hiv-1 Integrase Inhibitors Publisher Pubmed



Sirous H1, 2 ; Fassihi A1 ; Brogi S3, 4, 5 ; Campiani G3, 4 ; Christ F6 ; Debyser Z6 ; Gemma S3, 4 ; Butini S3, 4 ; Chemi G3, 4 ; Grillo A3, 4 ; Zabihollahi R7 ; Aghasadeghi MR7 ; Saghaie L1 ; Memarian HR8
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
  2. 2. Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, Siena, 53100, Italy
  4. 4. European Research Centre for Drug Discovery and Development (NatSynDrugs), via Aldo Moro 2, Siena, 53100, Italy
  5. 5. Department of Pharmacy, DoE Department of Excellence 2018-2022, University of Naples Federico II, via D. Montesano 49, Naples, 80131, Italy
  6. 6. Laboratory of Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
  7. 7. Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
  8. 8. Department of Chemistry, Faculty of Sciences, University of Isfahan, Isfahan, 81746-73441, Iran

Source: Medicinal Chemistry Published:2019


Abstract

Background: Despite the progress in the discovery of antiretroviral compounds for treating HIV-1 infection by targeting HIV integrase (IN), a promising and well-known drug target against HIV-1, there is a growing need to increase the armamentarium against HIV, for avoiding the drug resistance issue. Objective: To develop novel HIV-1 IN inhibitors, a series of 3-hydroxy-pyrane-4-one (HP) and 3-hydroxy-pyridine-4-one (HPO) derivatives have been rationally designed and synthesized. Methods: To provide a significant characterization of the novel compounds, in-depth computational analysis was performed using a novel HIV-1 IN/DNA binary 3D-model for investigating the binding mode of the newly conceived molecules in complex with IN. The 3D-model was generated using the proto-type foamy virus (PFV) DNA as a structural template, positioning the viral polydesoxyribonucleic chain into the HIV-1 IN homology model. Moreover, a series of in vitro tests were performed including HIV-1 activity inhibition, HIV-1 IN activity inhibition, HIV-1 IN strand transfer activity inhibition and cellular toxicity. Results: Bioassay results indicated that most of HP analogues including HPa, HPb, HPc, HPd, HPe and HPg, showed favorable inhibitory activities against HIV-1-IN in the low micromolar range. Particularly halogenated derivatives (HPb and HPd) offered the best biological activities in terms of reduced toxicity and optimum inhibitory activities against HIV-1 IN and HIV-1 in cell culture. Conclusion: Halogenated derivatives, HPb and HPd, displayed the most promising anti-HIV profile, paving the way to the optimization of the presented scaffolds for developing new effective antiviral agents. © 2019 Bentham Science Publishers.
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