Background: Oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has been highlighted as a
therapeutic target for anticancer drug design.
Objective: Target compounds were designed to address the effect of different substitution patterns at the N atom
of the carboxamide moiety on the bioactivity of this series.
Methods: Synthesis of the targeted compounds, crystallography, biological evaluation tests against human colon
carcinoma (HCT-116), and Glide docking studies.
Results: A new series of N-substituted- 4-hydroxy-2-quinolone-3-carboxamides was prepared and characterized
by means of FT-IR, 1H and 13C NMR, and elemental analysis. In addition, the identity of the core nucleus 5 was
successfully characterized with the aid of X-ray crystallography. Biological activity of prepared compounds was
investigated in vitro against human colon carcinoma (HCT-116) cell line. Results revealed that these compounds
inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA
cellular content. Compounds 7, 14, and 17 which have H-bond acceptor moiety on p-position displayed promising
PI3Kα inhibitory activity. On the other hand, derivatives tailored with bulky and hydrophobic motifs (16 and
18) on o- and m-positions exhibited moderate activity. Molecular docking studies against PI3Kα and caspase-3
showed an agreement between the predicted binding affinity (ΔGobsd) and IC50 values of the derivatives for the
caspase-3 model. Furthermore, Glide docking studies against PI3Kα demonstrated that the newly synthesized
compounds accommodate PI3Kα kinase catalytic domain and form H-bonding with key binding residues.
Conclusion: The series exhibited a potential PI3Kα inhibitory activity in HCT-116 cell line.