Identifying New Isatin Derivatives with GSK-3β Inhibition Capacity through Molecular Docking and Bioassays

Britto, Karolinni Bianchi; Francisco, Carla Santana; Ferreira, Débora; Borges, Bárbara Juliana Pinheiro; Conti, Raphael; Profeti, Demetrius; Rodrigues, L. R.; Lacerda, Valdemar; Morais, Pedro Alves Bezerra; Borges, Warley de Souza

doi:10.21577/0103-5053.20190206

Cited by 6 publications

(4 citation statements)

References 30 publications

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“…Eugenol was isolated from clove essential oil, according to the standard procedure [37] using hydrodistillation. The synthetic procedures used to obtain compounds 1a‐e follow the methodology described by Britto et al (2020) with modifications. Scheme 1 shows the synthesis of eugenol compounds.…”

Section: Methodsmentioning

confidence: 99%

Anti‐Candida, docking studies, and in vitro metabolism‐mediated cytotoxicity evaluation of Eugenol derivatives

et al. 2022

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The high morbidity and mortality rates of Candida infections, especially among immunocompromised patients, are related to the increased resistance rate of these species and the limited therapeutic arsenal. In this context, we evaluated the anti-Candida potential and the cytotoxic profile of eugenol derivatives.Anti-Candida activity was evaluated on C. albicans and C. parapsilosis strains by minimum inhibitory concentration (MIC), scanning electron microscopy (SEM), and molecular docking calculations at the site of the enzyme lanosterol-14-αdemethylase active site, responsible for ergosterol formation. The cytotoxic profile was evaluated in HepG2 cells, in the presence and absence of the metabolizing system (S9 system). The results indicated compounds 1b and 1d as the most active ones. The compounds have anti-Candida activity against both strains with MIC ranging from 50 to 100 μg ml −1 . SEM analyses of 1b and 1d indicated changes in the envelope architecture of both C. albicans and C. parapsilosis like the ones of eugenol and fluconazole, respectively. Docking results of the evaluated compounds indicated a similar binding pattern of fluconazole and posaconazole at the lanosterol-14-αdemethylase binding site. In the presence of the S9 system, compound 1b showed the same cytotoxicity profile as fluconazole (1.08 times) and compound 1d had 1.23 times increase in cytotoxicity. Eugenol and other evaluated compounds showed a significant increase in cytotoxicity. Our results suggest compound 1b as a promising starting point candidate to be used in the design of new anti-Candida agent prototypes.

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Section: Methodsmentioning

confidence: 99%

Anti‐Candida, docking studies, and in vitro metabolism‐mediated cytotoxicity evaluation of Eugenol derivatives

et al. 2022

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“…Generally indirubins are known to be ATP-competing inhibitors of several kinases by the formation of hydrogen bonds between the nitrogen group and the ATP binding site of the kinase 47 . Although some related substances with substituents at the amidic nitrogen could be identified which act similarly (GSK-3β inhibition by some N -substituted isatins) 48 , this seems not to be the case for KD87 and KD88. Our investigations on GSK-3β show, that from our 3 compounds only I3M inhibits the enzyme.…”

Section: Discussionmentioning

confidence: 97%

Synergistic effect of plasma-activated medium and novel indirubin derivatives on human skin cancer cells by activation of the AhR pathway

Rebl

Sawade

Hein

et al. 2022

Sci Rep

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Due to the increasing number of human skin cancers and the limited effectiveness of therapies, research into innovative therapeutic approaches is of enormous clinical interest. In recent years, the use of cold atmospheric pressure plasma has become increasingly important as anti-cancer therapy. The combination of plasma with small molecules offers the potential of an effective, tumour-specific, targeted therapy. The synthesised glycosylated and non glycosylated thia-analogous indirubin derivatives KD87 and KD88, respectively, were first to be investigated for their pharmaceutical efficacy in comparison with Indirubin-3'-monoxime (I3M) on human melanoma (A375) and squamous cell carcinoma (A431) cells. In combinatorial studies with plasma-activated medium (PAM) and KD87 we determined significantly decreased cell viability and cell adhesion. Cell cycle analyses revealed a marked G2/M arrest by PAM and a clear apoptotic effect by the glycosylated indirubin derivative KD87 in both cell lines and thus a synergistic anti-cancer effect. I3M had a pro-apoptotic effect only in A431 cells, so we hypothesize a different mode of action of the indirubin derivatives in the two skin cancer cells, possibly due to a different level of the aryl hydrocarbon receptor and an activation of this pathway by nuclear translocation of this receptor and subsequent activation of gene expression.

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“…The N-alkylated 1 – 4 and triazole 5 – 9 isatin derivatives (Figure ) were previously synthesized by our group …”

Section: Methodsmentioning

confidence: 99%

“…1) were previously synthesized by our group. 27 The synthesis of novel triazole derivatives (10−17) (Scheme 1) was carried out in a 10 mL glass vessel, in the presence of alkynyl 1 (0.1 g, 0.5 mmol), and synthesized or commercially available azides (2.1 mmol), sodium ascorbate (0.05 mmol), and 150 μL of copper sulfate (0.1 M solution), in DMF (2 mL) under microwave irradiation (150 W) for 10 min at 70 °C. After completion, the DMF was removed under vacuum.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Synthesis and Phytotoxic Evaluation of Isatin Derivatives Supported by 3D-QSAR Study

Morais

Britto

Messias

et al. 2022

J. Agric. Food Chem.

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Concerned about weed infestation, a major threat to food production and herbicide resistance that interferes in the mechanism of action of the main herbicides, we have synthesized eight isatin derivatives using the “Click Chemistry” approach through copper-catalyzed azide–alkyne cycloadditions (CuAAC). Sixteen isatin derivatives were evaluated for their phytotoxic activity against the seed culture of the model plants, Lactuca sativa and Allium cepa. Six of them showed phytotoxic activity similar to the positive control, trifluralin. Hypocotyl length measurement analysis in L. sativa revealed that triazole derivative 8 is more active than trifluralin. For A. cepa, root length measurement analyses revealed that 3, 10, 14, 16, and 17 were similar to the positive control trifluralin. Three-dimensional quantitative structure–activity relationship (3D-QSAR) comparative molecular field analysis (CoMFA) model construction using the acetolactate synthase (ALS) crystallographic structure displayed pk i values of predicted inhibitory activity and contour maps revealing sterically bulky groups for 11, the CF3 group in ortho, and for 17, Br in ortho, favoring the inhibitory ALS activity.

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Identifying New Isatin Derivatives with GSK-3β Inhibition Capacity through Molecular Docking and Bioassays

Cited by 6 publications

References 30 publications

Anti‐Candida, docking studies, and in vitro metabolism‐mediated cytotoxicity evaluation of Eugenol derivatives

Anti‐Candida, docking studies, and in vitro metabolism‐mediated cytotoxicity evaluation of Eugenol derivatives

Synergistic effect of plasma-activated medium and novel indirubin derivatives on human skin cancer cells by activation of the AhR pathway

Synthesis and Phytotoxic Evaluation of Isatin Derivatives Supported by 3D-QSAR Study

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