Synthesis,antiproliferative activity, 3D-QSAR,and molecular docking studies of novel L-carvone-derived pyrimidine-urea compounds

To explore novel natural product-based nitrogen-containing heterocyclic compounds with antiproliferative activity, 20 L-carvone-derived pyrimidine-urea compounds 4a–4t were synthesized through the multi-step reaction of L-carvone, and structurally characterized by Fourier transform infrared (FT-IR), hydrogen-1 nuclear magnetic resonance (¹H-NMR), Carbon-13 nuclear magnetic resonance (¹³C-NMR), and High-resolution mass spectrometry (HRMS). Besides, the in vitro antiproliferative activity of the target compounds against HepG2, Hela, and MCF-7 cells was evaluated by methyl thiazolyl tetrazolium (MTT) assay. According to the results, the target compounds showed certain inhibitory activities against the tested cancer cell lines, and five compounds ( 4b , 4h , 4k , 4l , and 4t ) exhibited better inhibition activities against Hela cells than the positive control ( 5-FU ). Among them, compound 4b held significant antiproliferative activities against Hela and HepG2 cells, and thus deserved further study as a leading compound of new anticancer drugs. In addition, an effective and reasonable three-dimensional quantitative structure-activity relationships (3D-QSAR) model was built by the Comparative molecular field analysis (CoMFA) method to analyze the relationship between the structures of the target compounds and their antiproliferative activities (expressed as pIC₅₀) against Hela cells, and proven to have good predictive ability. Molecular docking was carried out to study the possible binding modes of compound 4b and Survivin, and it was found that compound 4b could be well embedded into the active site, along with the formation of several hydrogen bonds and hydrophobic interactions.