SYNTHESIS, CHARACTERIZATION, BIOASSAY AND DENSITY FUNCTIONAL THEORY STUDIES OF CATIONIC IRON HALF SANDWICH COMPLEXES OF SELECTED HETEROFUNCTIONAL ACTIVE PHARMACEUTICAL AGENTS
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Date
2020-02
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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, [ษณ
5
-
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 gramnegative 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.