Synthesis and characterisation of novel phenanthroline quinone derivatives and their evaluation as Alzheimer's disease therapeutic active ingredients

Publication Type:
Thesis
Issue Date:
2018
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The study is based on the synthesis, characterisation and biological evaluation of series of new derivatives of phen-5,6-dione potentially could act as inhibitors for acetylcholinesterase (AChE) from electric eel and butyrylcholinesterase (BuChE) from equus horse serum and as an active pharmacophore inhibitors of acetylcholinesterase and butyrylcholinesterase. Twenty four derivatives of phen-5,6-dione were prepared including imine-Schiff based of phen-5,6-dione and 2-amino phenol as mono and di substituted active ingredient, condensation products of phen-5,6-dione with thiosemicarbazide, semicarbazide hydrochloride, hydroxylamine hydrochloride, aminoguanidine hydrochloride, aminoguanidine bicarbonate, 4-methyl-3-thiosemicarbazide, 2-methyl-3-thiosemicarbazide, 4-methyl-3-thiosemicarbazide, 4,4-di methyl-3-thiosemicarbazide, 4-ethyl-3-thiosemicarbazide, 4-phenyl-3-Thiosemicarbazide, ethylenediamine, hydrazine sulfate, o-nitro anline, diethylamine carbamyl chloride, o-phenylenediamine and benzyl amine. All the prepared compounds were characterised by various advanced techniques: ¹H NMR, ¹³ C NMR, FT-IR, ATR and HRMS and digital melting point. Ellman Assays were performed with acetylthiocoline iodide (ATCI) and s-butyrylthiocholine iodide (BTCI) as the substrate, using Galantamine and Tacrine, well-known AChE and BuChE inhibitors as the positive controls. IC₅₀ for the prepared compounds were determined. The study includes determination of several important kinetic parameters such as type of inhibition (Competitive) and Inhibition constant (Ki). The inhibition mechanism for determination of the activity of both AChE and BuChE inhibitors were extracted from Lineweaver- Burk plots and Dixon plots. Furthermore the drug-like properties were assessed based on Lipinski five rules and by utilising ADMET properties such as Aqueous solubility, Blood-brain barrier (BBB), CYP2D6 binding, Hepatotoxicity, Intestinal Absorption and PPB descriptors for each of studied compounds. Furthermore all the prepared active ingredients were sent for screening at QLD University. The simulation studies for molecular modelling of the obtained experimental results were assimilated with implementing Accelrys Discovery Studio 4.5 suite. The obtained data from the docking study were used for analysing the biological properties obtained in this study and some suggestions are stated. We found ability of the prepared compounds as active ingredient as chelating ligands to form complexes with Cu⁺² and Zn⁺² were investigated using UV–Vis spectroscopy. Similarities in absorption spectra including π–π*intra ligand transitions and a strong metal –ligand charge transfer (MLCT) in the visible region were observed. The obtained results support the idea that the phen-5,6-dione structure and electronic properties of these ligands incorporate features of both diamine and quinone ligands. These characteristics may be beneficial in decreasing the rate of cognitive decline in moderate to severe AD patients. This technique may provide useful information to investigators with relation to chemical profiling of drug seizures, however its use should be limited to that of a screening method. This technique demonstrate that a rational structure based on phen-5,6-dione derivatives can generate a molecules that can target modulate multiple factors, and provide a new tool to investigate Alzheimer’s disease.
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