Ultrasound-Assisted Synthesis of Substituted Chalcone-Linked 1,2,3-Triazole Derivatives as Antiproliferative Agents: In Vitro Antitumor Activity and Molecular Docking Studies

The synthesis of (<i>E</i>)-1-(1-benzyl-5-methyl-1<i>H</i>-1,2,3-triazol-4-yl)-3-phenyl-2-propen-1-one derivatives was carried out in two steps, using benzylic chloride derivatives as starting material. The structural determination of intermediates and final products was performed by spectroscopic methods: infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectrometry (IR, NMR, and MS). In vitro evaluation of cytotoxic activity on adherent and non-adherent cells showed that triazole chalcones exhibited significant activity against three of the five cell lines studied: non-Hodgkin lymphoma U937, glioblastoma multiform tumor T98G, and gallbladder cancer cells Gb-d1. In contrast, the cytotoxic activity observed for cervical cancer HeLa and gallbladder adenocarcinoma G-415 was considerably lower. Additionally, in the cell lines where activity was observed, some compounds demonstrated an In vitro inhibitory effect superior to that of the control, paclitaxel. Molecular docking studies revealed specific interactions between the synthesized ligands and therapeutic targets in various cell lines. In U937 cells, compounds <b>4a</b> and <b>4c</b> exhibited significant inhibition of vascular endothelial growth factor receptor (VEGFR) kinase, correlating with their biological activity. This effect was attributed to favorable interactions with key residues in the binding site. In T98G cells, compounds <b>4r</b> and <b>4w</b> showed affinity for transglutaminase 2 (TG2) protein, driven by their ability to form hydrophobic interactions. In Gb-d1 cells, compounds <b>4l</b> and <b>4p</b> exhibited favorable interactions with mitogen-activated protein kinase (MEK) protein, similar to those observed with the known inhibitor selumetinib. In HeLa cells, compounds <b>4h</b> and <b>4g</b> showed activity against dihydrofolate reductase (DHFR) protein, driven by hydrogen bonding interactions and favorable aromatic ring orientations. On the other hand, compounds <b>4b</b> and <b>4t</b> exhibited no activity, likely due to unfavorable interactions related to halogen substitutions in the aromatic rings.