Design, synthesis, structural characterization and in vitro evaluation of new 1,4-disubstituted-1,2,3-triazole derivatives against glioblastoma cells

Silva, Veronica D. da; Faria, Bruna Mafra de; Colombo, Eduardo H.; Ascari, Lucas M.; Freitas, Gabriella P A de; Flores, Leonã S.; Cordeiro, Yraima; Romão, Luciana; Buarque, Camilla D.

doi:10.1016/j.bioorg.2018.10.003

Cited by 36 publications

(19 citation statements)

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“…Compound 40 indicated large H-bond acceptor peaks directed towards the tosyl and azide groups, suggesting a stronger acceptor region. 79 A novel series of 1,2,3-triazole-dithiocarbamate 41 was obtained, which act as anticancer agents against four cancer cell lines as compared to the standard drug 5-uorouracil because of the presence of electronegative atoms at the ortho-position of the benzyl ring. 80 Gregorić et al synthesized a series of pyrimidine-2,4-dione-1,2,3-triazole and furo[2,3-d]pyrimidine-2-one-1,2,3-triazole as the anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: review

et al. 2020

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Section: Introductionmentioning

confidence: 99%

CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: review

et al. 2020

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“…The 1,4-disubstituted-1,2,3-triazole derivatives 1 – 10 were previously synthesized by copper-catalyzed azide-alkyne cycloaddition reaction, as described by Silva et al 2019 [ 24 ]. All the compounds were structurally characterized by the 1 H NMR, 13 C NMR and mass spectrometry techniques.…”

Section: Methodsmentioning

confidence: 99%

“…The triazole compound family is also known for its potential activity against fungi [21] and trypanosomatids, such as parasites of the genus Leishmania [22,23]. We recently carried out the design, synthesis, and structural characterization of new 1,4-disubstituted-1,2,3-triazole compounds by copper-catalyzed azide-alkyne click chemistry reaction [24]; however, its antileishmanial potential has not yet been elucidated. Triazole compounds were planned to correlate the effect of the exchange of functional groups of aldehydes by classical privileged groups such as sulphonylhydrazones, hydrazones, and coumarin with anticancer and antileishmanial activity [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

“…We recently carried out the design, synthesis, and structural characterization of new 1,4-disubstituted-1,2,3-triazole compounds by copper-catalyzed azide-alkyne click chemistry reaction [24]; however, its antileishmanial potential has not yet been elucidated. Triazole compounds were planned to correlate the effect of the exchange of functional groups of aldehydes by classical privileged groups such as sulphonylhydrazones, hydrazones, and coumarin with anticancer and antileishmanial activity [24][25][26]. These groups can also act in synergism with the 1,2,3-triazole nucleus and potentiate the pharmacological activity.…”

Section: Introductionmentioning

confidence: 99%

“…These groups can also act in synergism with the 1,2,3-triazole nucleus and potentiate the pharmacological activity. The triazole group has interesting physical-chemical and chemical properties that can mimic the characteristics of different functional groups [13,24].…”

Section: Introductionmentioning

confidence: 99%

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1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in Leishmania amazonensis Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study

Almeida-Souza

Silva

et al. 2020

IJMS

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The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties. Ten compounds were analyzed, with compound 6 notably presenting IC50: 14.64 ± 4.392 µM against promastigotes, IC50: 17.78 ± 3.257 µM against intracellular amastigotes, CC50: 547.88 ± 3.256 µM against BALB/c peritoneal macrophages, and 30.81-fold selectivity for the parasite over the cells. It also resulted in a remarkable decrease in all the parameters of in vitro infection. Ultrastructural analysis revealed lipid corpuscles, a nucleus with discontinuity of the nuclear membrane, a change in nuclear chromatin, and kinetoplast swelling with breakdown of the mitochondrial cristae and electron-density loss induced by 1,4-disubstituted-1,2,3-triazole treatment. In addition, compound 6 enhanced 2.3-fold the nitrite levels in the Leishmania-stimulated macrophages. In silico pharmacokinetic prediction of compound 6 revealed that it is not recommended for topical formulation cutaneous leishmaniasis treatment, however the other properties exhibited results that were similar or even better than miltefosine, making it a good candidate for further in vivo studies against Leishmania parasites.

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Understanding the origin of reactivity, mechanism and regioselectivity of the [3+2] cycloaddition reaction between nitrile imine and pyrrolopyrazine

Hamdaoui

Nacereddine

Djerourou

2022

J of Physical Organic Chem

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In this work, we have performed a computational study on the [3+2] cycloaddition (32CA) reaction between nitrile imine and pyrrolopyrazine within molecular electron density theory (MEDT) using B3LYP and M06-2X DFT functionnals together with 6-31G(d,p) basis set. This study shows that the popular B3LYP is the appropriate functional for performing this study. The analysis of energy profiles indicates that this 32CA reaction favours kinetically the formation of a single product as observed experimentally. The favour cycloadduct (P 1 ) is formed through a moderate polar stepwise mechanism, in which the first step is the determining one that is characterised by a moderate polarity and the second step by a highly polar character, while the unfavoured one is formed via a nonpolar one-step asynchronous mechanism. Solvent effects do not change the regioselectivity, but it increases the activation energies. Thermodynamic parameters analysis indicates that this 32CA reaction is characterised by an exothermic and endergonic characters favouring the formation of cycloadduct (P 1 ), as observed experimentally. Conceptual DFT (CDFT) reactivity indices analysis shows that pyrrolopyrazine 2 reacts as a nucleophile, while nitrile imine 3 as an electrophile. Local reactivity descriptors, such as Parr functions and dual descriptors, show that this 32CA reaction is regioselective leading to the formation of P 1 . Analysis of ELF electron density demonstrated that the interaction between the high electron density reactive centre with that of low electron density leads to the formation of P 1 cycloadduct. The obtained results using MEDT method are in great agreement with what observed in the experimental data.

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Design, synthesis, structural characterization and in vitro evaluation of new 1,4-disubstituted-1,2,3-triazole derivatives against glioblastoma cells

Cited by 36 publications

References 51 publications

CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: review

CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: review

1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in Leishmania amazonensis Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study

Understanding the origin of reactivity, mechanism and regioselectivity of the [3+2] cycloaddition reaction between nitrile imine and pyrrolopyrazine

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