Complexation of drug amifampridine with Cu(II), Zn(II) and Cd(II) ions, and its dimerization with the magic of Mn(II) salts. Potential anti-COVID-19 and anticancer activities.

Abstract

The different behaviors of the drug amifampridine (AMP) against Mn(II), Cu(II), Zn(II) and Cd(II) metal ions, in the presence and absence of tris(2-aminoethyl)amine (tren) was studied. The results showed that AMP successfully coordinates with Cu(II), Zn(II) and Cd(II) metal ions, but interestingly it undergoes an unexpected dimerization through a C-H activation in the presence of different Mn(II) salts. A four-coordinate complex of zinc(II), [Zn(AMP)2Cl2] (1), a binuclear complex of cadmium(II), [Cd2(AMP)2Cl4] (2), three five-coordinate tren-based metal complexes, [Cu(tren)(AMP)](ClO4)2 (8), [Zn(tren)(AMP)]Cl2 (9) and [Cd(tren)(AMP)](ClO4)2 (10), three pyridinium salts, [AmpDimer]X (X = Cl-, NO3-, ClO4-; (3, 4 & 5)), and also two four-coordinate metal complexes with this pyridinium cation, [Zn(AmpDimer)Cl3] (6) and [Cd(AmpDimer)Cl3] (7), were synthesized. All new compounds were characterized by elemental analysis and IR spectroscopy, and by 1H- and 13C-NMR spectroscopy (for 1, 2, 3, 6, 7, 9 & 10) and by X-ray crystal structure determinations (for 1, 3, 4, 5, 7, 8 & 10). Theoretical studies showed that the [M(tren)(AMP)]2+ cations act as pH-sensitive drug carriers of AMP and release it upon protonation. The molecular docking studies on the interaction of AMP and the above complexes/salts with DNA and the proteins of SARS-CoV-2 showed that the synthesized complexes/salts have greater anticancer and anti-covid-19 activities than AMP alone.