1,5-Disubstituted-1,2,3-Triazoles as GABA analogues: Synthesis, QSAR and biological evaluation as Pseudomonas fluorescens GABA-AT inhibitors

Abstract

We report the synthesis of a new series of γ-aminobutyric acid (GABA) analogues as possible GABA-AT inhibitors, where the nitrogen at the Ƴ-position is contained in a 1,5-disubstituted-1,2,3-triazole ring system. The triazole ring system was assembled by the Ru(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (RuACC) protocol. GABA-AT inhibition activity was predicted by means of a QSAR model that was constructed in this work. Different molecular descriptors families were employed for its construction, like steric type ($Wap$ and $PW5$), solubility type ($\Delta \text{PSA}$), and electronic type ($\Delta {Triazole}_3$). Additionally, a similarity analysis based on the electronic profile of 1,5-triazole and 1,4-triazole GABA analogues was done to support the QSAR predictions. Finally, the three best candidates were biologically tested as Pseudomonas fluorescens GABA-AT inhibitors showing an inhibition percent compared to FDA approved inhibitors.