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

Sevinçli Z. Ş., Bildirici N., Cetin A., Bildirici İ.

CHEMISTRYSELECT, vol.8, no.35, pp.202302683, 2023 (SCI-Expanded)

  • Publication Type: Article / Article
  • Volume: 8 Issue: 35
  • Publication Date: 2023
  • Doi Number: 10.1002/slct.202302683
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED)
  • Page Numbers: pp.202302683
  • Van Yüzüncü Yıl University Affiliated: Yes


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.