Computational Design, Chemical Synthesis, and Bioevaluation of Pyrimidinyl‐Indoles for Targeting Breast Cancer Cells

Abstract Cancer is a global health challenge, despite significant advancements in research. Addressing this issue, we report the design, synthesis and biological evaluation of pyrimidinyl indoles as potential antineoplastic agents. Pyrimidinyl indoles interact with pyruvate kinase isoform M2 (PKM2), which is commonly overexpressed in oral, lung, breast and colorectal cancers. In silico studies indicated that these molecules are having affinity towards PKM2 and targeting key residues such as Phe26, Leu27, Tyr390, Gln393, Leu394 and Glu397 at the interfacial active site region between the two chains of PKM2. Thereafter compounds were designed, synthesized and characterized using nuclear magnetic resonance (NMR), infrared spectroscopy (IR) and mass spectrometry (MS). This was followed by in vitro screening using cell lines and enzyme‐coupled assays. One of the designed PKM2 inhibitor demonstrated potent anticancer activity against MCF‐7 (Breast Cancer) cells while sparing normal MCF‐10 A breast cells. Molecular dynamics (MD) simulation studies showed that the developed inhibitor stabilized the PKM2 active site over a 100 ns simulation.