1,4-Disubstituted-1,2,3-triazole GABA Analogues: Synthesis, In Vitro Evaluation, Quantum QSAR and Molecular Docking against Pseudomonas fluorescens GABA-AT

We report the synthesis of a new series of γ-aminobutyric acid (GABA) analogues where the nitrogen at the ɣ-position is contained in a 1,4-disubstituted-1,2,3-triazole ring system. The triazole ring system was assembled by the Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuACC) protocol. We have identified two active compounds with 43 and 59 % inhibition respectively. A descriptive quantum QSAR study was carried out to correlate this activity with the structural changes in the GABA scaffold. The inhibitory activity of the compounds is related to the electronic properties of the triazole ring and substituents. The interaction with P. fluorescens GABA-aminotransferase (GABA-AT) was evaluated by molecular docking, using a homology model of the biological target. One compound showed the best interaction energy, the thiophene- substituted triazole 26 c, with a value that correlates well with the experimental inhibition results. The triazole ring is determinant for a proper orientation for interaction with the GABA-AT enzyme. In addition, the molecular docking revealed the importance of a hydrophobic pocket near the PLP prosthetic group and how this pocket can be used to improve the inhibitory activity of GABA analogues. Human GABA-AT molecular docking studies of these analogues showed their great potential as competitive inhibitors of this enzyme.