Antitumor activity of rhodanine derivatives: Quantitative structure-activity relationship and molecular docking study

Rhodanines have been reported to possess antibacterial, antiviral, antimalarial, antifungal, and antitumor activity. A series of novels rhodanine derivatives were assayed for their cytotoxic activity against a panel of human cancer cell lines. Quantitative structure-activity relationship (QSAR) analysis was performed on the anticancer activity against cutaneous T lymphocyte (cell line Hut-78) since 98 % of compounds have achieved the concentration achieving 50% cell growth inhibition (GI50) 100 μM. QSAR study of the anticancer activity against HUT-78 achieved the model that satisfies the fitting and internal cross-validation criteria (N = 28 ; R2 = 0.75 ; Q2 LOO = 0.64): logGI50 = 2.51 – 3.46 MATS2e – 1.05 MATs7e – 0.15 RDF060p Descriptors included in the model revealed the importance of the presence of atoms with higher polarizability in the outer region of molecules. Molecules that possess 3- methoxy group (ALR9) and 3-bromine (ALR16) at the benzene ring proved to be potential drug candidates against human T cell lymphoma since inhibited 50% growth of cells Hut-78 at the very low concentration (3 and 7.5 μmol dm-3, respectively). Also, the presence of electronegative atoms at the topological distances 2 and 7, such as hydroxyl and ethoxy groups as substituents of the benzylidene group decreases the activity. A molecular docking study confirmed the findings of the QSAR study regarding the structural features related to the inhibition of nonreceptor proteintyrosine kinase (c-Src) (PDB ID: G6H) and indicated importance of the oxygen atoms from phenoxy and rhodanine groups, and rhodanine sulphur atoms as hydrogen bond acceptors in key interactions with binding site residues, as well as benzene rings in generations of van der Waals interactions. Our study suggests that rhodanine derivatives could be developed as novel tyrosine kinase inhibitors in the treatment of leukemia.