Design, Synthesis and In Vitro Evaluation of Novel Anti-HIV 3-Pyrazol-3- yl-Pyridin-2-One Analogs

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Organic Synthesis

Background:

• Natural products show anti-HIV potential but can be toxic.
• Derivatization and combination of pharmacophores can reduce toxicity and enhance potency.
• Exploring novel chemical scaffolds is crucial for developing new anti-HIV agents.

Purpose of the Study:

• To design and synthesize novel pyrazol-pyridone compounds.
• To predict drug-likeness and ADMET properties in silico.
• To evaluate the anti-HIV-1 activity of the synthesized compounds.

Main Methods:

• Pyrazol-pyridones were designed by integrating known anti-HIV pharmacophoric fragments.
• In silico analysis guided the selection of compounds for synthesis.
• Seventeen novel pyrazol-pyridones were synthesized and tested for anti-HIV-1 activity.

Main Results:

• Designed compounds exhibited favorable drug-likeness (QED > zidovudine) and predicted safety profiles (noncarcinogenic, nonmutagenic).
• Compound 6q showed significant anti-HIV-1 activity with an IC50 of 6.14 µM against HIV-1VB59.
• Compound 6l also demonstrated anti-HIV-1 activity with IC50 values below 20 µM.

Conclusions:

• Compound 6q is the most potent pyrazol-pyridone derivative identified, with a therapeutic index of 54.31 against HIV-1VB59.
• This study reports the anti-HIV-1 activity of the pyrazol-pyridone class for the first time.
• The pyrazol-pyridone scaffold represents a novel chemical class for further exploration in anti-HIV drug development.