New α-Hydroxy-1,2,3-triazoles and 9H-Fluorenes-1,2,3-triazoles: Synthesis and Evaluation as Glycine Transporter 1 Inhibitors

• Published in: Journal of the Brazilian Chemical Society Vol. 31; no. 6; pp. 1258 - 1269
• Main Authors: da Silva, Veronica, Silva, Rafaela, Gonçalves Neto, João, López‑Corcuera, Beatriz, Guimarães, Marilia, Noël, François, Buarque, Camilla
• Format: Journal Article
• Language: English
• Published: Sociedade Brasileira de Química 01-06-2020
• Subjects: CHEMISTRY, MULTIDISCIPLINARY; glycine transport; click chemistry; 9H-fluorenes-1,2,3-triazoles; schizophrenia; 1,4-disubstituted-1,2,3-triazoles; Friedel-Crafts alkylation
• ISSN: 0103-5053; 1678-4790
• DOI: 10.21577/0103-5053.20200011

Two series of new compounds containing 1,2,3-triazole moiety were designed as putative GlyT1 inhibitors aiming the discovery of new hits with activity in cognitive disorders. 1,4-Disubstituted α-hydroxy-1,2,3-triazoles were obtained as racemates in moderate to good yields by the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction (click chemistry) as the key step between propargyl alcohols and aryl azides, previously prepared from anilines or boronic acids. Benzo[c]chromene-triazoles were planned to be obtained by palladium-catalyzed C−H activation using [bis(trifluoroacetoxy)iodobenzene] (PhI(TFA)2) of some α-hydroxy-1,2,3-triazoles, since benzo[c]chromenes are also privileged groups with several biological activities, including to the central nervous system. Unexpectedly, 9H-fluorenes-1,2,3-triazoles, instead of benzo[c]chromene-triazoles, were obtained by Friedel-Crafts alkylation reaction. The two series of compounds were tested for inhibition of the glycine transporter (rat GlyT1 isoform) but only the α-hydroxy-1,2,3-triazole 9b was active (half maximal inhibitory concentration (IC50) = 8.0 µM).