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

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

Baseline characteristics of newly diagnosed HIV-1 infected patients in Iran.

1<p>Information on gender, age, and city of residence were obtained from all 50 cases who completed the questionnaire.</p>2<p>Information on marital status and transmission route were obtained from 35 cases who completed questionnaires.</p>3<p>Infection with hepatitis C virus and hepatitis B virus were tested in 30 and 28 cases, respectively.</p

Prevalence of drug resistance-associated mutations among 47 sequenced samples.

<p>IAS-USA, the international Antiviral society-USA; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; SDRMs, surveillance drug-resistant mutations.</p

Phylogenetic trees of sequenced Iranian samples.

<p>(A) protease, (B) reverse transcriptase, (C) integrase, (D) gag, and (E) env. Trees were constructed using neighbour joining method with 1000 replicates. Two sequences each of 6 HIV-1 subtypes retrieved from the GenBank are included as references. Open circles (○) indicate the reference sequence of CRF35_AD, open squares (□) indicate subtype A1, open triangles (▵) indicate A2, open diamonds (◊) indicate subtype D, closed circles (•) indicate subtype B, and closed squares (▪) indicate CRF01_AE. Bootstrap values over 70% are shown.</p