Design and Synthesis of New Combretastatin A-4 Derivatives Containing Naphthothiophene Based on the Structural Rigidification Strategy

Six new combretastatin A-4 derivatives containing a naphtho[2,3-b]thiophene-4,9-dione core were successfully synthesized via a two-step procedure. This approach involved a multi-component reaction to generate dihydrofuranonaphthoquinone intermediates, followed by a sulfur-mediated oxidative transformation of the dihydrofuran scaffold into the corresponding thiophene derivatives. The structures of all synthesized compounds were characterized using IR, ¹H-NMR, and ¹³C-NMR spectroscopy. In vitro cytotoxicity assays against the A549 lung cancer cell line revealed that five out of the six derivatives exhibited moderate to strong growth inhibitory activity, with IC₅₀ values ranging from 3.40 ± 0.24 to 46.46 ± 1.63 µM. Notably, the fluorinated analogues 4b and 4c demonstrated the most potent cytotoxicity, with IC₅₀ values of 3.40 ± 0.24 and 3.69 ± 0.35 µM, respectively. Molecular docking simulations indicated that compound 4c accommodates effectively within the colchicine-binding site (CBS) of tubulin through a cooperative multi-point interaction mechanism, where polar anchoring and hydrophobic packing work synergistically to stabilize the ligand–protein complex. Despite satisfying standard drug-likeness criteria, computational ADME profiling highlighted that the high hydrophobicity and poor water solubility of 4c remain major physicochemical hurdles. Overall, these combretastatin A-4 derivatives represent a novel class of bioactive scaffolds with promising potential for further structural optimization in anticancer drug development.