Background: Natural products have shown potent anti-HIV activity, but some of these
also possess toxicity. The pharmacophoric fragments of these natural products have scope of combination
with other pharmacophoric fragment and derivatization to reduce toxicity and increase the
potency. Combination of natural product fragments from different classes of anti–HIV compounds
may lead to a new class of potent anti–HIV agents.
Objective: Design, in silico prediction of drug-likeness, ADMET properties and synthesis of pyrazol–
pyridones. Evaluation of the anti–HIV–1 activity of synthesized pyrazol–pyridones.
Method: Pyrazol–pyridones were designed by combining reported anti–HIV pharmacophoric
fragments. Designed molecules were synthesized after in silico prediction of drug-likeness and
ADMET properties. Compounds were evaluated for activity against HIV–1VB59 and HIV–1UG070.
Result: QED value of designed pyrazol–pyridones was greater than the known drug zidovudine.
The designed compounds were predicted to be noncarcinogenic and nonmutagenic in nature. Seventeen
novel pyrazol–pyridones were synthesized with good yield. Compound 6q and 6l showed
activity with IC50 values 6.14 μM and 15.34 μM against HIV–1VB59 and 16.21 μM and 18.21 μM
against HIV–1UG070, respectively.
Conclusion: Compound 6q was found to be most potent among the synthesized compounds with a
therapeutic index of 54.31against HIV–1VB59. This is the first report of anti–HIV–1 activity of
pyrazol–pyridone class of compounds. Although the anti–HIV–1 activity of these compounds is
moderate, this study opens up a new class for exploration of chemical space for anti–HIV–1 activity.