Iron (III) triflate catalyzed, one-pot three-component synthesis of novel α-aminophosphonate of 5-hydrazineyl-2-(phenylsulfonyl)pyridine as potent antiproliferative agents against MCF-7 and HCT-116: In vitro and in silico investigations on molecular

Cancer statistics over the past decade reveal a significant global burden, with increasing incidence and mortality rates. Among the most commonly diagnosed cancers are colorectal and breast cancer. The present work aims to design new drug-like compounds as potential agents against colorectal and breast cancer, using the Kabachnik–Fields reaction as a synthetic approach. α-Aminophosphonate phenylsulfonyl derivatives (4a–f) were synthesized via a one-pot, three-component reaction involving 5-hydrazineyl-2-(phenylsulfonyl)pyridine (1), benzaldehyde derivatives (2a–f), and diethyl phosphite (3). Reaction conditions were optimized using various Lewis acids, with iron(III) trifluoromethanesulfonate identified as the most effective catalyst, affording excellent yields in a short time. The novel derivatives were characterized using FT-IR, 1 H NMR, 13 C NMR, 31 P NMR, and mass spectrometry. The in vitro antiproliferative activity of the α-aminophosphonates was evaluated against two human cancer cell lines: breast (MCF-7) and colon (HCT-116), using Doxorubicin (DM2) as a standard and the MTT assay for comparison. Compounds 4b and 4e emerged as selectively potent antiproliferative candidates against the HCT-116 cell line, while all compounds showed significantly lower cytotoxic activity against the MCF-7 cell line. In silico molecular docking simulations of compounds 4b, 4e and DM2 with CDK2 (PDB: 8FP0) were performed using GNINA software. The results revealed that both compounds occupy the same region of DM2 and interact with the ATP-binding site, suggesting a potential to affect CDK2 function. Notably, compound 4e exhibited more extensive hydrophobic interactions, indicating a stronger binding affinity compared to 4b. Molecular dynamics simulations supported these findings, showing that compound 4b did not remain stably bound to CDK2 throughout the simulation period.