Design, synthesis, in silico studies and antiproliferative evaluation of some novel hybrids of pyrimidine-morpholine.

Introduction: Cancer is a complex group of diseases characterized by the uncontrolled growth and spread of abnormal cells in the body. These cells can invade nearby tissues and organs, or they may metastasize to other parts of the body through the bloodstream or lymphatic system.

Methods: In this study, eight novel pyrimidine-morpholine hybrides (2a-2h) were designed and synthesized based on molecular hybridization approach to identify potent cytotoxic agents. Spectroscopic methods, including infrared spectroscopy (IR), proton and carbon nuclear magnetic resonance (¹HNMR & ¹³CNMR), and mass spectrometry, were employed to confirm the structures of the compounds. The cytotoxic effects of the derivatives were evaluated against cancerous cell lines, including MCF-7 and SW480, using the MTT assay.

Results and discussion: It was demonstrated that all derivatives had appropriate cytotoxic potential with IC₅₀ in range of 5.12-117.04 μM. Compound 2g was identified as the most potent compound, exhibiting IC₅₀ values of 5.10 ± 2.12 μM and 19.60 ± 1.13 μM toward the SW480 and MCF-7 cell lines, respectively. Cell cycle analysis showed that 2g could induces phase arrest in MCF-7 breast cancer cells. The apoptosis assay demonstrated the induction of apoptosis in the SW480 cell line. The biological activity of the compounds was confirmed by the docking studies. DFT analysis for compounds 2g and 2h was conducted at the B3LYP/6-31+G** level of theory. It was concluded that 2g is both thermodynamically and kinetically more stable than 2h. Moreover, the interpretation of ADME (Absorption, Distribution, Metabolism, and Excretion) indicates that these new series of compounds possess acceptable prognostic physicochemical properties. These synthesized compounds may serve as promising candidates for further investigation as anticancer agents.