Design, Synthesis, in silico studies and Antiproliferative Evaluation of Some Novel Hybrids of Pyrimidine-Morpholine

Soghra Khabnadideh ^1* Elaheh Ataollahi ¹ Leila Emami ¹ Al-Anood Mohammad Al-Dies ² fateme zare ¹ Alireza Poustforoosh ¹ Mina Emami ¹ Fateme Saadat ¹ Fateme Motamen ¹ Zahra Rezaei ¹

• ¹ Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
• ² Umm al-Qura University, Mecca, Saudi Arabia

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. 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 anti-cancer agents.