Design, Docking Simulations, Synthesis, and in vitro and in vivo Behavioral Assessment of m-Aminobenzoic Acid Analogues as GABA-AT Inhibitors

γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter whose deficiency is related to affections involving overexcited neurons (e. g., anxiety and epilepsy); rise of GABA levels by inhibition of GABA-aminotransferase (GABA-AT) is a treatment option. The aim of this contribution was to assess a series of m-aminobenzoic acid derivatives (analogous to GABA) as GABA-AT inhibitors. Chosen compounds from docking simulations, were synthesized in good yields by green chemistry, tested in vitro for inhibition of GABA-AT and assayed for protection against pentylenetetrazole (PTZ) induced seizures, and ability to counter picrotoxin (PTX) induced anxiety. These compounds had a lower binding energy (higher affinity) than GABA and GABA-AT inhibitor vigabatrin (VGB) at the model active site. DABA_2 a (3,5-dimaleamilbenzoic acid) had excellent attributes in silico (ΔG=−9.00 kcal/mol vs −5.33 kcal/mol of VGB), good competitive inhibition of GABA-AT in vitro (K_I=3.6×10⁻⁶ M, ΔG=−7.42 kcal/mol) and a low acute toxicity (≥1,000 mg/kg) with good protection against PTZ and PTX (100 mg/kg), leading to stablish the good modulation of GABAergic transmission in vivo.