Design, synthesis and network pharmacology-integrated evaluation of benzenesulfonamides as potential Dickkopf-1 (Dkk-1)-targeting anticancer candidates.

Sulfanilamide-based drugs are known to exhibit immense anti-cancer activities, and thus, we sought to design and formulate sulfanilamide derivatives in order to study their potential against carbonic anhydrase II, pancreatic elastase, Dickkopf-1 (Dkk1) and LRP6 proteins, which are potential anti-cancer targets for various cancers. Out of all the synthesized derivatives, compound 4d exhibited significant inhibitory potential against CA-II, with an IC50 value of 0.348 ± 0.024 µM, which is about 3-fold higher than that of the reference drug acetazolamide (IC50 = 0.9979 ± 0.0024 µM). The significance of Dkk1 was taken into consideration in this study. Molecular docking interaction studies revealed that compound 4d exhibited good binding potential with CA-II, pancreatic elastase, LRP6 and Dkk1, with binding energies of -8.1, -8.7, -7.9 and -10.4 kcal mol-1, respectively. Furthermore, in the course of DNA binding experiments, compound 4d exhibited the highest binding constant value of 2.3 × 107 mol-1, validating the other biological tests, and these results are in agreement with the reported values, demonstrating the significance of compound 4d to act as a representative drug in the future. Finally, the present work has the potential to pave way for new therapeutic approaches in cancer treatment with the involvement of the less explored Dkk1 signaling target. In addition, a network pharmacology analysis of compound 4d against pancreatic cancer identified 243 shared targets that converged, through protein-protein interactions and enrichment analyses, on the PI3K-AKT and receptor tyrosine kinase signalling axes, providing a system-level rationale for its anticancer potential.