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

Silva, Veronica D. da; Silva, Rafaela R.; Neto, João Gonçalves; López-Corcuera, Beatriz; Guimarães, Marília Zaluar P.; Noël, François; Buarque, Camilla D.

doi:10.21577/0103-5053.20200011

Cited by 3 publications

(3 citation statements)

References 23 publications

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“…The triazole compounds and derivatives were synthesized in the “Laboratório de Síntese Orgânica” (LSO) and physiochemically characterized as described previously [ 37 , 38 ]. The remaining compounds were purchased from commercial sources at the analytical grade: VX-770 (#HY-13017), genistein (#HY-14596), forskolin (Fsk, #HY-15371), and CFTR channel inhibitor (CFTRinh-172, #16671) are from MedChemExpress (Monmouth Junction, NJ, USA); while VX-445 (#S8851) is from Selleckchem (Houston, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Bacalhau

Ferreira

Silva

et al. 2023

JPM

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The R334W (c.1000C>T, p.Arg334Trp) is a rare cystic fibrosis (CF)-causing mutation for which no causal therapy is currently approved. This mutation leads to a significant reduction of CF transmembrane conductance regulator (CFTR) channel conductance that still allows for residual function. Potentiators are small molecules that interact with CFTR protein at the plasma membrane to enhance CFTR-dependent chloride secretion, representing thus pharmacotherapies targeting the root cause of the disease. Here, we generated a new CF bronchial epithelial (CFBE) cell line to screen a collection of compounds and identify novel potentiators for R334W-CFTR. The active compounds were then validated by electrophysiological assays and their additive effects in combination with VX-770, genistein, or VX-445 were exploited in this cell line and further confirmed in intestinal organoids. Four compounds (LSO-24, LSO-25, LSO-38, and LSO-77) were active in the functional primary screen and their ability to enhance R334W-CFTR-dependent chloride secretion was confirmed using electrophysiological measurements. In silico ADME analyses demonstrated that these compounds follow Lipinski’s rule of five and are thus suggested to be orally bioavailable. Dose–response relationships revealed nevertheless suboptimal efficacy and weak potency exerted by these compounds. VX-770 and genistein also displayed a small potentiation of R334W-CFTR function, while VX-445 demonstrated no potentiator activity for this mutation. In the R334W-expressing cell line, CFTR function was further enhanced by the combination of LSO-24, LSO-25, LSO-38, or LSO-77 with VX-770, but not with genistein. The efficacy of potentiator VX-770 combined with active LSO compounds was further confirmed in intestinal organoids (R334W/R334W genotype). Taken together, these molecules were demonstrated to potentiate R334W-CFTR function by a different mechanism than that of VX-770. They may provide a feasible starting point for the design of analogs with improved CFTR-potentiator activity.

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Section: Methodsmentioning

confidence: 99%

Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Bacalhau

Ferreira

Silva

et al. 2023

JPM

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“…The synthesis of 1,2,3-triazole derivative compounds was carried out by the CuAAC reaction, as described previously by da Silva et al, 2020 . Structural elucidation was performed by high-resolution mass spectroscopy and nuclear magnetic resonance techniques ( 1 H NMR and 13 C NMR).…”

Section: Methodsmentioning

confidence: 99%

“…The synthesis of 1,2,3-triazole derivative compounds was carried out by the CuAAC reaction, as described previously by da Silva et al, 2020. 53 Structural elucidation was performed by high-resolution mass spectroscopy and nuclear magnetic resonance techniques ( 1 H NMR and 13 C NMR). Compounds are proven to be >95% pure by high-performance liquid chromatography (HPLC) analysis (additional details are given in Supporting Information Figure S1).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Nitric Oxide Induction in Peritoneal Macrophages by a 1,2,3-Triazole Derivative Improves Its Efficacy upon Leishmania amazonensis In Vitro Infection

et al. 2021

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1,2,3-Triazole is one of the most flexible chemical scaffolds broadly used in various fields. Here, we report the antileishmanial activity of 1,2,3-triazole derivatives, the ultrastructural alterations induced by their treatment, and the nitric oxide (NO) modulation effect on their efficacy against Leishmania amazonensis in vitro infection. After the screening of eleven compounds, compound 4 exhibited better results against L. amazonensis promastigotes (IC50 = 15.52 ± 3.782 μM) and intracellular amastigotes (IC50 = 4.10 ± 1.136 μM), 50% cytotoxicity concentration at 84.01 ± 3.064 μM against BALB/c peritoneal macrophages, and 20.49-fold selectivity for the parasite over the cells. Compound 4 induced ultrastructural mitochondrial alterations and lipid inclusions in L. amazonensis promastigotes, upregulated tumor necrosis factor α, interleukin (IL)-1β, IL-6, IL-12, and IL-10 messenger RNA expressions, and enhanced the NO production, verified by nitrite (p = 0.0095) and inducible nitric oxide synthase expression (p = 0.0049) quantification, which played an important role in its activity against intramacrophagic L. amazonensis. In silico prediction in association with antileishmanial activity results showed compound 4 as a hit compound with promising potential for further studies of new leishmaniasis treatment options.

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