Introduction. GABA is the major inhibitory neurotransmitter in the CNS. Due to its low degree of lipophilicity, it cannot cross the blood brain barrier and is not considered an efficient drug therapy. In this context, the synthesis of the GABA analogues with increased lipophilicity and promising therapeutic potential has been the subject of intensive research. Results and discussion. Chemistry. In this work, we present the synthesis of some structural analogues of GABA where the nitrogen atom is embedded in a triazole heterocyclic ring system designed as GABA-aminotransferase (GABA-AT) inhibitors. The synthesis of analogues 7A-10A was accomplished via a copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) followed by basic hydrolysis. For the synthesis of analogues 2B1-5B4 and 2B5-5B8 the same methodology. In a subsequent step, the conjugate addition of i-butyl and pClC6H4 cuprates to 2Bi-5Bi and 2Bp-5Bp followed by basic hydrolisis of the corresponding esters afforded the analogues final. Preliminary tests of enzyme inhibition on GABA-AT Pseudomonas fluorescens. Preliminary tests were performed to determine the inhibitory potential of 7A-10A, 2B1-5B4 and 2B5-5B8 analogues compared to the positive controls Vigabatrin (VGB) and valproic acid at a final concentration of 0.8 mM. According to the Figure, the absorbance value of GABA represents 100% of catalytic activity, therefore the absorbance of VGB represents a percentage activity of 52% and 48% inhibition, for valproic acid, 68% activity and 32% inhibition. According to these data analogues 8A and 2B1 show a 35% and 34% degree of inhibition compared with the positive control valproic acid (32%), 2B5 and 4B7 show a 43% and 59% degree of inhibition compared with the positive control VGB (48%). Conclusions. We have developed an optimal procedure for the synthesis of the triazole-derived analogues 7A-10A, 2B1-5B4 and 2B5-5B8. Our preliminary inhibitory potential results found that the compounds 8A, 2B1, 2B5 and 4B7 are the most promising GABA-AT inhibitors to further its development as new drugs.

Synthesis of triazole as GABA analogues

254th National Meeting (2017)

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