No abstract

Alzheimer's disease is a neurodegenerative condition that decreases cognitive function. Thus, intense research efforts have focused on developing acetylcholinesterase (AChE) inhibitors with less side effects. The aim of this study was to synthesize aminobenzoic acid derivatives and test their AChE inhibitory capacity in silico and in vitro. Ten electron-poor aminobenzoic acid derivatives were synthesized in good-high yields. Their interaction with EeAChE, according to docking simulations, is mainly mediated by the aromatic ring of the ligands and the catalytic triad of the receptor (π-π interactions). The in vitro evaluation revealed mixed inhibition (mostly competitive) in all cases. The structural analysis showed better Ki values for heterocyclic than linear compounds and with the presence of two carboxylic groups attached. 5-Aminoisophthalic acid (AIPA_3, K I = 73 μM) showed the lowest K I of all compounds. The electron-poor aromatic ring of the test compounds is recognized by the electron-rich peripheric and catalytic binding sites of AChE. AIPA_3, with the best properties, is a promising lead compound for developing new AChE 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 maminobenzoic 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 = À 9.00 kcal/mol vs À 5.33 kcal/mol of VGB), good competitive inhibition of GABA-AT in vitro (K I = 3.6 × 10 À 6 M, ΔG = À 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.