GABA–AT Inhibitors: Design, Synthesis, Pharmacological Characterization, Molecular Docking and ADMET Studies

Abstract γ‐aminobutyric acid (GABA) is the main neuroinhibitory transmitter and a non‐proteinogenic amino acid in the brain. When the brain concentration of GABA diminishes below a threshold level, it can cause excess neuronal excitation and lead to convulsions. γ‐Aminobutyric acid aminotransferase (GABA‐AT) is an enzyme that catalyzes the conversion of GABA to succinic semialdehyde in the GABA shunt pathway and responsible for breaking down GABA in the brain. By inhibiting GABA‐AT activity, it may be possible to increase the levels of GABA in the brain and reduce the likelihood of seizures. Herein, the synthesis and evaluation of α‐pyrazolo‐(aryl/alkyl)methyl‐ketone and pyrazolo[5,1‐a]isoquinoline derivatives were carried out anticonvulsant activity, with a focusing on GABA‐AT inhibition. In total, 20 novel compounds were synthesized, and characterized with binding assays at GABA‐AT receptor, in the 0.060±0.01 to 5.99±0.10 micromolar range. The ADMET predictions and drug‐like characteristics of α‐pyrazolo‐(aryl/alkyl)methyl‐ketone and pyrazolo[5,1‐a]isoquinoline compounds were identified by pharmacokinetic investigations. Furthermore, the predicted analogue‐enzyme complexes with docking scores were in the range of −7.3 to −10.5, and their SAR analysis was found to be significant of α‐pyrazolo‐(aryl/alkyl)methyl‐ketone and pyrazolo[5,1‐a]isoquinoline structures in medicinal chemistry. Our results revealed that this new structural information will be useful for the future design and synthesis of activity‐based GABA‐AT inhibitors.