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