Design, synthesis, molecular docking and cytotoxic evaluation of novel pyrimidine-based sulfonamide derivatives as potent anticancer agents: SAR insights and biological profiling.

The low selectivity and significant toxicity of current chemotherapeutic medicines make the research and development of novel anticancer agents an urgent necessity. This study used IR, NMR, MS, and elemental studies to rationally design, synthesize, and structurally characterize a novel class of pyrimidine-based sulfonamide derivatives. A wide variety of heterocyclic scaffolds, such as oxadiazoles, thiazolinones, chromenes, pyrazoles, pyrazolopyrimidines, triazolopyrimidines, imidazolidines, and triazines, were made possible by the synthetic approach. HepG2, MCF-7, WI-38, and VERO cell lines were used to test the synthetic compounds’ cytotoxic properties. With IC50 values ranging from 7.4 to 10.2 µg/mL against HepG2 and 8.2 to 10.0 µg/mL against MCF-7, compounds 18, 21, 23, and 24 showed extremely significant anticancer activity, nearly matching the potency of the reference medication 5-fluorouracil. Crucially, these substances showed a good therapeutic index with noticeably reduced toxicity toward normal WI-38 and VERO cells. The most active derivatives’ increased cytotoxicity and selectivity were shown to be largely due to electron-donating groups, balanced lipophilicity, and optimal heterocyclic substitution patterns, according to structure–activity relationship (SAR) research. The experimental results were corroborated by molecular docking experiments against thymidylate synthase (PDB: 2VF5), where compound 23 exhibited the highest binding affinity (S = − 5.5589 kcal/mol), creating strong H-bond interactions with Lys487 and Ala498 within the active region. Overall, compounds 18, 21, 23, and 24 are identified as interesting lead candidates for additional development as effective and selective anticancer medicines based on the combined biology, SAR, and docking results. Future optimization, mechanistic research, and even in vivo assessment can all benefit from these discoveries.