In silico molecular docking, ADME study and synthesis of new 1,3-diazetidin-2-one derivatives with high anti-proliferative activity

Abstract

Background: Cancer and inflammation are strongly connected; tumor growth and spread are also greatly influenced by inflammation. Nitrogen-based heterocycle analogs are excellent suppliers of pharmaceuticals. Quaternary rings play a bigger role in drug development as bioactive scaffolds. For improved tolerance and synergistic benefits, heterocyclic nitrogen rings are present in many anticancer medications. Understanding how to bind to the EGFR and its prospective impacts on cancer cells, expect to construct new heterocyclic compounds that may help produce potent anticancer medicines with a high safety profile. Methods: Novel 1,3-diazetidin-2-one derivatives were designed, synthesized from mefenamic acid, and their cytotoxic activity against a lung cancer cell line (A549) was initially tested in vitro. These compounds were anchored to the crystal structure of the epidermal growth factor receptor (PDB code 1M17) in a molecular docking study to determine their binding affinity at the active site. The newly synthesized derivatives were verified and confirmed by elemental analysis and spectroscopic data (FT-IR, 1H-NMR, and 13C-NMR). In addition, physicochemical, drug-like, and toxicological predictions were performed for these derivatives. Results: Based on a molecular docking study, all compounds (M4a-e) demonstrated superior PLPfitness (84.70, 85.89, 91.90, 88.61, and 92.77, respectively) to erlotinib (76.20). The anti-proliferation evaluation of the A549 cell line revealed that compounds M4c and M4e had exceptional and promising anti-proliferative activity on this cell line to treat lung cancer, with IC50 values of 1.75 µm and 2.05 µm at 72 hours, respectively, making them significantly more active than the reference erlotinib, which had an IC50 value of 11.5 µm at 72 hours. Conclusions: The cytotoxicity investigation and the molecular docking study showed a robust association with the novel compounds (M4a-e). Suggest a comprehensive pharmacological survey to understand how these newly created chemicals combat cancer fully.