Co(II), Cu(II) Complexes of 4‐Methyl‐ N ‐(pyridin‐4‐yl)benzenesulfonamide: Can Electronic Reactivity Predict Bioactivity and Does Coordination Confer New Properties?

Metal coordination can substantially modify the electronic structure of organic ligands, with potential consequences for their biological properties. Here, the electronic structure and predicted bioactivity of the previously reported sulfonamide ligand 4‐methyl‐ N ‐(pyridin‐4‐yl)benzenesulfonamide (HL) and its Co(II) and Cu(II) complexes were investigated using DFT and PASS analysis, respectively. Previously reported experimental characterization and antibacterial data were used as the reference framework for the computational analysis. Coordination substantially reorganized the electronic structure of HL. The HOMO–LUMO gap decreased from 5.41 eV (HL) to 3.46 eV ([Co(L) 2 ]) and 2.96 eV ([Cu(L) 2 ]), with decreased chemical hardness and increased softness; changes were greatest for [Cu(L) 2 ]. HL was inactive against Escherichia coli , Salmonella Typhi , and Staphylococcus aureus , while both complexes showed antibacterial activity. [Co(L) 2 ] produced greater inhibition than [Cu(L) 2 ] against E. coli and S. aureus , despite the greater electronic reactivity of [Cu(L) 2 ]. Calculated frontier‐orbital energies and global reactivity descriptors alone did not account for the metal‐dependent biological response observed in this system. PASS analysis showed coordination altered the predicted biological activity profile. Electronic reactivity and biological activity may not always align. Computed global descriptors indicate electronic potential, while spatial orbital distribution may provide additional insight into the observed biological response.