Abstract
A new series, of γ-amino butyric acid analogs were designed and synthesized as novel potent GABA-AT inhibitors. A structure–activity relationship study was performed by correlating the effect of different substituents with GABA-AT inhibitory activity of the title compounds. The preliminary bioassays showed that acid hydrazones exhibited excellent inhibitory activities in micromolar (0.07–0.56 μM) range, while Schiff’s bases showed variable results. The most potent compound, 4-amino-N′-[(1Z)-1-(2-bromophenyl)ethylidene]butanehydrazide (AHG177) showed inhibitory potency (IC50) of 0.073 μM. Aminobutyrate transaminase is a pyridoxal-P enzyme which follows a bi–bi ** pong mechanism and in pyridoxamine form can readily transaminate only with succinic semialdehyde and 2-oxoglutarate. The results strongly suggest that only the pyridoxal form of the enzyme is capable of reacting with the ligands. Our findings open up the possibility to extend this protocol to different databases in order to find new potential inhibitor for promising targets based on a rational drug design process.
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Author wishes to thank Vice Chancellor, Birla Institute of Technology, Mesra, Ranchi and Chairman, Bharat Institute of Technology, Meerut to provide necessary infrastructural and other facilities.
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Figure S1
3D crystal structure of GABA-AT
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Bansal, S.K., Sinha, B.N. & Khosa, R.L. γ-Amino butyric acid analogs as novel potent GABA-AT inhibitors: molecular docking, synthesis, and biological evaluation. Med Chem Res 22, 134–146 (2013). https://doi.org/10.1007/s00044-012-0023-0
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DOI: https://doi.org/10.1007/s00044-012-0023-0