Chalcogen bond-assisted syn-locked scaffolds: DFT analysis and biological implications of novel tubulin inhibitors

A series of new tubulin inhibitors containing chalcogen bonds have been discovered. Density functional theory (DFT) analysis of the O–C–C–S torsion profile shows a preference of 0.8 kcal/mol for the syn-conformer over the anti-conformer. Besides, the O–S natural bond orbital (NBO) analysis reveals that the OLP ∼ C-SBD∗ energy potential is 0.62 kcal/mol. Further pharmacochemical screening of several series of (4-arylthiophen-2-yl)(3,4,5-trimethoxyphenyl)methanones identified IPO-10 as a highly effective tubulin inhibitor with an IC50 of 23 nm for MCF-7. [Display omitted] •Chalcogen bond assisted syn-locked scaffolds of (4-arylthiophen-2-yl)(3,4,5-trimethoxyphenyl)methanones.•The DFT calculations characterized the properties of intramolecular chalcogen bond.•Compound TPO-10 exhibited excellent antiproliferative activities against MCF-7.•Some pharmacological experiments were conducted to verify the possible mechanism of TPO-10.