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
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