⟪Green-Ligand⟫ in Metallodrugs Design-Cu(II) Complex with Phytic Acid: Synthetic Approach, EPR-Spectroscopy, and Antimycobacterial Activity

The interaction of sodium phytate hydrate C6H18O24P6<middle dot>xNa<middle dot>yH2O (phytNa) with Cu(OAc)2<middle dot>H2O and 1,10-phenanthroline (phen) led to the anionic tetranuclear complex [Cu4(H2O)4(phen)4(phyt)]<middle dot>2Na+<middle dot>2NH4+<middle dot>32H2O (1), the structure of the latter was determined by X-ray diffraction analysis. The phytate 1 is completely deprotonated; six phosphate- fragments (with atoms P1-P6) are characterized by different spatial arrangements relative to the cyclohexane ring (1a5e conformation), which determines two different types of coordination to the complexing agents-P1 and P3, P4, and P6 have monodentate, while P2 and P5 are bidentately bound to Cu2+ cations. The molecular structure of the anion complex is stabilized by a set of strong intramolecular hydrogen bonds involving coordinated water molecules. Aromatic systems of phen ligands chelating copper ions participate in strong intramolecular and intermolecular pi-pi interactions, further contributing to their association. At the supramolecular level, endless stacks are formed, in the voids of which sodium and ammonium cations and water molecules are present. The stability of 1 in the presence of human serum albumin (HSA) was investigated using Electron Paramagnetic Resonance (EPR) spectroscopy. Continuous wave (CW) EPR spectra in water/glycerol frozen solution clearly indicate a presence of an exchange-coupled Cu(II)-Cu(II) dimeric unit, as well as a Cu(II) monomer-like signal arising from spins sufficiently distant from each other, with comparable contributions of two types of signals. In the presence of albumin at a 1:1 ratio (1 to albumin), the EPR spectrum changes significantly, primarily due to the reduced contribution of the S = 1 fraction showing dipole-dipole splitting. The biological activity of 1 in vitro against the non-pathogenic (model for Mycobacterium tuberculosis) strain of Mycolicibacterium smegmatis is comparable to the first-line drug for tuberculosis treatment, rifampicin.