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

Veronica Da Silva,Rafaela Silva,François Noël,João Gonçalves Neto,Beatriz López‑Corcuera,Camilla Buarque,Marilia Guimarães

doi:10.21577/0103-5053.20200011

Abstract

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).

Highlights

In a previous work,[18] we described the use of 1,2,3-triazoles as linker to combine different groups in a bifunctional molecules active for cancer human glioblastoma cells (GBM), including highly drugresistant human cell lines GBM-02 and GBM-95
The conditions of Pd-catalyzed C−O bond did not lead to the expected benzo[c]chromene-triazoles but to new 9H-fluorenes-1,2,3-triazoles by Friedel-Crafts alkylation reaction
All the synthesized compounds were evaluated as glycine transporter (GlyT1) inhibitors

Summary

Introduction

Different reports indicate that triazoles have affinity for dopaminergic, adrenergic and serotonergic receptors[4,6] and inhibit the glycine transporter GlyT1, considered as an important target for the treatment of schizophrenia, cognitive disorders, alcohol dependence and Bitopertin (2) (Hoffmann-La Roche) was the first of the non-sarcosine derivative GlyT1 inhibitors to be tested in schizophrenia preclinical models and phase II and III clinical trials.[11] This compound is a potent and selective non-competitive inhibitor of the GlyT1 subtype and does not act on other molecular targets.[12] Among the compounds containing a triazole moiety, methyl-1,2,3-triazole 3 stands out since it is a non-competitive inhibitor with very high potency and good metabolic stability in vitro.[9] It is important to notice that among the compounds evaluated by these authors,[9] the 1,2,3-triazoles were more potent than.

Methods

Results

Conclusion