Nicotinamide complexes of metal(II) furan-2-carboxylates: synthesis, determination of crystal structures, Hirshfeld surface analysis, and in vitro and in silico evaluation of inhibitory properties on CA I, CA II, AChE, BChE, and GR enzymes

In this study, nicotinamide complexes of Cu2⁺, Co2⁺, and Zn2⁺ furan-2-carboxylates were synthesized, and the crystal structures of the complexes were characterized by single crystal X-ray diffraction. The chemical composition and functional groups of the complexes were confirmed using elemental analysis, Fourier transform infrared spectroscopy (FT-IR), ultraviolet–visible region (UV–Vis) spectroscopy, and mass spectrometry (MS). Hirshfeld surface analysis detailed the intermolecular interactions present in the crystal structures of the complexes. The complexes feature a central six-coordinate ion (Cu2⁺, Co2⁺, or Zn2⁺) located on an inversion center, which is bonded to two N atoms from nicotinamide and four O atoms from water molecules. There is a furan 2-carboxylate anion that is not coordinated with metal atoms but links to complex structures via hydrogen bonds. Within the scope of biochemical studies, the inhibitory effects of the synthesized complexes on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase I and II (hCA I, hCA II), and glutathione reductase (GR) enzymes were investigated by spectrophotometric methods. It was determined that the complexes, especially Complex 2, exhibited strong enzyme inhibition properties. Molecular docking analyses revealed the binding tendencies and binding energies of the complexes to the active sites of the enzymes. Complex 2 has a high binding affinity with AChE, BChE, hCA I, hCA II, and GR enzymes, and these bindings were supported by hydrogen bonds and π-π interactions. ADMET predictions showed that the complexes have toxicologically safe profiles despite their pharmacokinetic limitations, such as low gastrointestinal absorption and inability to cross the blood–brain barrier. It was determined that the risks of hepatotoxicity, carcinogenicity, immunotoxicity, and mutagenicity were low. As a result, these metal complexes are evaluated as potential therapeutic agents in the treatment of diseases such as Alzheimer’s disease, glaucoma, epilepsy, malaria, and cancer. The data obtained in this study emphasize the biological activities and pharmacological potential of the complexes, and it is recommended that they be supported by future in vivo studies.