Synthesis, crystallographic, DNA binding, and molecular docking/dynamic studies of a privileged chalcone-sulfonamide hybrid scaffold as a promising anticancer agent.

In the present study, a drug-like molecular hybrid structure between chalcone and sulfonamide moieties was synthesized and characterized. The structural peculiarities of the synthesized hybrid were further verified by means of single crystal X-ray crystallography. Furthermore, its biological activity as an anticancer agent was evaluated. The synthesized model of chalcone-sulfonamide hybrid 3 was found to have potent anticancer properties against the studied cancer cell lines. Hence, the in vitro binding interaction of hybrid 3 with Calf thymus DNA (CT-DNA) was studied at a simulated physiological pH to confirm its anticancer activity for the first time. This was investigated by applying different spectroscopic techniques, ionic strength measurements, viscosity measurements, thermodynamics, molecular dynamic simulation and molecular docking studies. The obtained results showed a clear binding interaction between hybrid 3 and CT-DNA with a moderate affinity via a minor groove binding mechanism. The binding constant (Kb) at 298 K calculated from the Benesi-Hildebrand equation was found to be 3.49 × 104 M-1. The entropy and enthalpy changes (ΔS0 and ΔH0) were 204.65 J mol-1 K-1 and 35.08 KJ mol-1, respectively, indicating that hydrophobic interactions constituted the major binding forces. The results obtained from molecular docking and dynamic simulation studies confirmed the minor groove binding interaction and the stability of the formed complex. This study can contribute to further understanding of the molecular mechanism of hybrid 3 as a potential antitumor agent and can also guide future clinical and pharmacological studies for rational drug design with enhanced or more selective activity and greater efficacy.[Figure: see text]Communicated by Ramaswamy H. Sarma.