Background: Cancer is a leading cause of mortality worldwide. Discovery of small molecules as anticancer agents is an active area of research, as these molecules possess the remarkable ability to interact with specific targets within cancer cells. Objectives: In vitro anticancer activity of six hit derivatives from a series of 2-phenyl-substituted 4-amino–6, 7-dihydro-5H-cyclopentadpyrimidines was tested against human cancer cell lines, viz., A549 (human lung cancer) and A431 (human skin cancer). Methods: Cytotoxicity was evaluated for six hits by the standard MTT assay. Further, their effect on clonogenic potential and cell cycle was tested using colony forming assay and flow cytometric analysis, respectively. Apoptosis-inducing potential was confirmed using Caspase-3/7 Glo assay and detection of cleaved caspase-3 by immunofluorescence. The effect on cell migration was tested using a wound healing assay. Target analysis, Molecular docking and ADMET simulations were performed to identify molecular targets, interactions and assess pharmacokinetic profiles. Results: Specific derivatives showed good to moderate cytotoxicity against A549 and A431 (with average IC50 in the range of ~30 µM), and these hits led to apoptosis and G1 arrest in these cell lines, respectively. Furthermore, identified hits inhibited cell migration in A549 cells. Computational consensus target analysis identified EGFR and CDK2 as high-confidence targets. Docking studies indicated favorable interactions and stability, whereas the ADMET analysis confirmed the drug-likeness and optimal pharmacokinetic and safety profiles of the small molecules. Conclusions: Our current study demonstrates the anticancer potential of novel pyrimidine derivatives. We envisage the use of these small molecules as promising anticancer agents, particularly in skin and non-small cell lung cancer.
Aware et al. (Wed,) studied this question.