Synthesis, Characterization, Bioassay and Density Functional Theory Studies of Cationic Iron Half Sandwich Complexes of Selected Heterofunctional Active Pharmaceutical Agents

Abstract

The molecular modification of purely organic drugs by the incorporation of a metal atom is an active area of research. However, there is paucity of data in the use of half sandwich organometallic fragments and in particular the cationic iron half sandwich, [ɳ5-C5H5(CO)2Fe]+, in structural modification of drug molecules. The cationic iron half sandwich organometallic fragment provides a metal centre that could participate in biochemical reactions with potentially the desirable benefit of conferring new or modified modes of action of the drug molecules. Therefore, the objective of this study was to modify the molecular structures of the active pharmaceutical agents (APAs); 3-aminosalicylic acid (3-ASA), 4-aminosalicylic acid (4-ASA), 5-aminosalicylic acid (5-ASA), terizidone (TZD), ethionamide (ETH), prothionamide (PTH) and linezolid (LZD) by the incorporation of the cationic iron half sandwich organometallic fragment. A two pronged approach involving molecular modelling and organometallic synthesis was employed. In molecular modelling, the molecular geometries of the seven selected drug molecules were optimized and their local and global reactivity indices calculated in order to predict their ligation behaviours towards the iron half sandwich. The most stable molecular geometries and spectroscopic properties of the seven active pharmaceutical agents and their organometallic complex salts were predicted computationally using the DFT functionals; B3LYP, CAM-B3LYP and PBEPBE and 6-311g(d,p), 6-311g(2d,p) and LANL2DZ basis sets in Gaussian 09 and 16. Experimentally, the iron half sandwich organometallic salts of the APAs were synthesized, purified and characterized by FT-IR spectroscopy, 1H and 13C NMR spectroscopy, and elemental analysis. Antibacterial susceptibility tests of the new compounds against selected gram-positive and gram-negative bacteria showed that the LZD and TZD complexes had good abilities to inhibit the growth of the tested bacteria with comparable or better growth inhibition ability than their corresponding free ligands. Furthermore, the incorporation of the cationic iron half sandwich organometallic moiety to 3-ASA, 4-ASA, 5-ASA, ETH and PTH conferred antibacterial activity against the selected bacterial strains hence broadening the drugs spectra of activity. Therefore, the structural modification of APAs by the incorporation of the iron half sandwich can be pursued as a means of enhancing the usefulness of drugs.