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Synthesis, Molecular Modelling and Biological Studies of 3-hydroxypyrane- 4-one and 3-hydroxy-pyridine-4-one Derivatives as HIV-1 Integrase Inhibitors

Author(s):

Hajar Sirous, Afshin Fassihi*, Simone Brogi*, Giuseppe Campiani, Frauke Christ, Zeger Debyser, Sandra Gemma, Stefania Butini, Giulia Chemi, Alessandro Grillo, Rezvan Zabihollahi, Mohammad R. Aghasadeghi, Lotfollah Saghaie and Hamid R. Memarian   Pages 1 - 16 ( 16 )

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.

Method: 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.

Keywords:

3-hydroxy-pyrane-4-one, 3-hydroxy-pyridine-4-one, HIV-1 IN inhibitors (HIV-1 INIs), Molecular modelling, anti-HIV agents

Affiliation:

Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Laboratory of Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Laboratory of Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, 81746-73461 Isfahan, Department of Chemistry, Faculty of Sciences, University of Isfahan, 81746-73441 Isfahan



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