Synthesis, X-ray structure and molecular modelling analysis of cobalt(ii), nickel(ii), zinc(ii) and cadmium(ii) complexes of the widely used anti-inflammatory drug meloxicam

Abstract

The reactions of cobalt(II)-, nickel(II)-, zinc(II)- and cadmium(II)-acetates with the widely used anti-inflammatory drug meloxicam (H₂mel, 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1dioxide) in methanol produced micro-crystalline solids which were collected and recrystallized from dimethylsulfoxide (dmso) solution to give crystals of trans,trans-[M^II(Hmel)₂(O-dmso)₂] (M = Co, 1; Ni, 2; Zn, 3; Cd, 4). The X-ray diffraction analyses showed that 1, 3 and 4 are isomorphous and isostructural. The two Hmel⁻ anions chelate the metal centre through the nitrogen atom from the thiazole ring and the amide oxygen atom at the equatorial positions, whereas the two dmso molecules link the metal at the apical sites through their oxygen atoms. The metal atom is pseudo-octahedrally co-ordinated, the M–O(amide) bond distances being 2.083(3), 2.081(4) and 2.269(2) Å, and the M–N(thiazole) lengths 2.088(3), 2.060(4) and 2.254(2) Å for 1, 3 and 4, respectively. The Hmel⁻ ligand adopts a ZZZ-conformation which is stabilised by a strong intramolecular O⋯H–N hydrogen bond and the conformation of the thiazine ring changes from a half-chair to an envelope. The ¹H NMR spectrum for 3 (298 K) shows well defined peaks, and the H(N) amide and H(thiazole ring) proton signals (9.66 and 7.43 ppm) experience significant effects upon deprotonation and metal ligation. The quantum mechanics semi-empirical ZINDO/1 method reproduces the structures of the ligand molecules (H₂mel and Hmel⁻) at an acceptable degree of accuracy except for the S–O bond distances. The computed complex-formation enthalpies at the gas phase for the model metal-chelates M^II(⁻O–CHCH–C(O)NH–(ring-CN–CHCH–S))⁺ (M = Co, Ni, Cu, Zn) are in the range −2711–−3228 kJ, much lower than the enthalpy of protonation of Hmel⁻ (−2094 kJ). The computed complex-formation enthalpy for the Cd(II)-chelate (−2158 kJ) is close to the enthalpy of protonation of Hmel⁻. The computed spectrum for Zn(⁻O–CHCH–C(O)NH–(ring-CN–CHCH–S))₂ has an intense effect only in the region 300–400 nm attributable to HOMO–LUMO + 1 or thiazole-to-enol charge transfer. The geometry optimisations at the density functional Becke3LYP/(Lanl2dz; 6-31G**, S) level reproduce very well the structures of H₂mel and the M(⁻O–CHCH–C(O)NH–(ring-CN–CHCH–S))₂ (M = Zn, Cd) moieties of 3 and 4, and produce a reliable structure for Cu(⁻O–CHCH–C(O)NH–(ring-CN–CHCH–S))₂. The complex molecules 1, 3 and 4 as well as the model bis-chelates are highly hydrophobic in the exterior surface; this suggests a facile cell membrane permeability and an inertness towards dissociation in aqueous media for the potential anti-inflammatory drugs 1 and 3.