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Ferrocene Based Anilides: Synthesis, Structural Characterization and Inhibition of Butyrylcholinesterase

Abstract

Twenty three compounds of two series of ferrocene based anilides, with general formula C5H5-Fe-C5H4-C6H4-NH-CO-C6H4-R (where R = H, F, Cl, CH3 and OCH3), have been successfully synthesized. The compounds were characterized by elemental analysis, FTIR, 1H NMR and 13C NMR spectroscopies. Two compounds (M07 and P09) were characterized by X-ray crystallography. Solid state studies indicate that ferrocene derivatives with conformation of the meta substituent of the amide engage in intermolecular H-bonding stabilizing the meta derivatives over the para analogues. The H-bonding takes place when the conformation of the ferrocene changes by rotation around the C-N bond favoring interactions between two molecules in adjacent layers in the solid state. The potential that this H-bonding would be important for the biological effects of these molecules was investigated using both experimental and computational studies. All compounds were found to inhibit butyrylcholinesterase. The most active compound shows 50% inhibition at a concentration of 9 ± 0.2 μM similar to the known drug Galantamine (with an IC50 of 8 μM). Compounds with the ferrocene meta to amide linkage were consistently found to be slightly more active than the other structural isomers suggesting that potential H-bonding was only able to increase the overall affinity for the protein slightly. The computational studies confirmed the limited effects of the H-bonding in the presence and absence of water in the active site of butyrylcholinesterase supporting the importance of hydrofobicity of inhibitors for this enzyme.

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Publication details

The article was received on 01 May 2018, accepted on 23 Jul 2018 and first published on 23 Jul 2018


Article type: Paper
DOI: 10.1039/C8DT01726C
Citation: Dalton Trans., 2018, Accepted Manuscript
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    Ferrocene Based Anilides: Synthesis, Structural Characterization and Inhibition of Butyrylcholinesterase

    A. A. Altaf, M. Hamayun, B. Lal, M. N. Tahir, A. A. Holder, A. Badshah and D. C. Crans, Dalton Trans., 2018, Accepted Manuscript , DOI: 10.1039/C8DT01726C

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