Background: Phosphoinositide 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. Objectives: Target compounds were designed to probe the significance of alcohol and imine moieties tailored on a benzoin scaffold to better understand the structure activity relation (SAR) and improve their biological activity as anticancer compounds. Methods: Chemical synthesis of the targeted compounds, biological evaluation tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, as well as Glide docking studies were employed in this investigation. Results: A new series of 1,2-diphenylimino ethanol was successfully synthesized and characterized by means of FT-IR, HRMS, NMR, and by elemental analysis. Biological screening revealed that the newly synthesized compounds inhibit PI3Kα activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines. Results additionally showed that these compounds exhibit selective antiproliferative activity, induce apoptosis, and suppress the VEGF production. Compounds 2b, 2d, and 2g displayed promising inhibitory activity in HCT-116 suggesting that hydrophobic and/or hydrogen bond-acceptor mediate(s) ligand-receptor interaction on o- and mpositions. Furthermore, compounds 2g, 2i, 2j, and 2h, bearing hydrophobic moiety on m- and pposition, exerted high antiproliferative activity in T47D and MCF-7 cells, whereas compound 2e showed selectivity against T47D and MCF-7. Molecular docking studies against PI3Kα and caspase-3 demonstrated a strong correlation between the predicted binding affinity (ΔGobsd) and IC50 values of prepared compounds for the caspase-3 model, implying that the cellulous inhibitory activity was caspase-3-dependent. Moreover, Glide docking against PI3Kα identified Ser774, Lys802, E849, V851, and Asp933 as key binding residues. Conclusion: The series exerted a potential PI3Kα inhibitory activity in human carcinoma cell lines expressing PI3Kα.

Background: Natural products are characterized by their chemical diversity and being a good source of a range of bioactive structures including antidiabetic compounds. Diabetes mellitus (DM) is considered a major worldwide health concern. Rational drug design has been widely accomplished, to discover and optimize innovative leads for different molecular targets of type 2 DM including α-glucosidase, PPARγ, DPP-IV, PTP1B, AR, GSK-3β, 11β-HSD1, GK, etc. Objective: This review illustrates the potential of natural products as a rich source of lead compounds for antidiabetic drug discovery with some examples of computational studies carried out to determine the possible molecular target, structure activity relationship, and further optimization chances. Conclusion: Natural products will remain an attractive source for researchers to explore their therapeutic potential against DM. Guided by the computational studies; systematic lead optimization via structural modifications will speed up the generation of potential new clinical candidates for the treatment of type 2 DM.

The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (¹H and ¹³C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds 8 (IC₅₀ Caco-2 = 98 µM, IC₅₀ HCT-116 = 337 µM) and 16 (IC₅₀ Caco-2 = 13 µM, IC₅₀ HCT-116 = 240.2 µM). Results showed that compound 16 significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues.