Design, Synthesis, Antiproliferative Screening, and In Silico Studies of Some Pyridinyl-Pyrimidine Candidates

Using pyrimidinethione, a new series of pyridinyl-pyrimidine candidates was prepared by reacting with diverse carbon-centered electrophiles like hydrazonoyl chloride, N-arylchloroacetamide, ethyl chloroacetate, and enaminone derivatives. Some heteroannulated compounds, such as triazolopyrimidine and thiazolopyrimidine derivatives were obtained. The mass fragmentation pathways were investigated by the electron impact mass spectrometry (EI-MS), and the molecular ion peaks (M^+.) were recorded at different intensities. The in vitro antiproliferative efficacy of the prepared compounds against MCF7 and HCT116 cancer cell lines showed the highest potency of pyrimidinethione 2, triazolopyrimidine 4, and thiazolopyrimidine 10. Also, in silico studies were performed to recognize these findings. A molecular docking simulation towards the EGFR enzyme showed the best docking score of thiazolopyrimidine 10 through H-bonding and hydrophobic interactions in comparison to the interactions of co-crystallized ligand and doxorubicin. With DFT calculations, compound 10 exhibited the lowest energy gap and the highest softness. Among ADME simulation, compounds 7, 8, 9, and 11 exhibited desirable lead-likeness. It is hoped that this work may affect advancing new effective antiproliferative agents.