A molecular orbital treatment of piroxicam and its M2+-complexes: The change of the drug configuration in a time of bond formation

Piroxicam is a non-steroidal anti-inflammatory and anti-arthritic drug. The global structure of piroxicam molecule H2PIR (4-hydroxy-2-methyl-N-2-pyridyl-2H-benzothiazine-3-carboxamide 1,1-dioxide) is behind the remarkable biological activity of the drug. The equilibrium geometry of the molecule is investigated by DFT calculations at the B3LYP/6-31G∗∗ level of the theory. The pronounced steric effects existing within the molecule create a non-planar structure with a dihedral angle −32.7° between the two units of molecule: substituted pyridine residue and benzothiazine ring. This steric hindrance makes the molecule quite labile and major changes occur in the configuration of the molecule when in presence of metal ions. B3LYP/6-31G∗∗ calculations on piroxicam and its metal-ion complexes [M(H2PIR)2]2+, M = Ni(II), Cu(II) and Zn(II), showed that the geometry of the drug in the free state differs significantly from that in the metal complex. In the time of metal ion-drug bond formation the drug switches-on from the closed structure (equilibrium geometry) to the open one.