Design, synthesis and biological evaluation of 1,5-disubstituted α-amino tetrazole derivatives as non-covalent inflammasome-caspase-1 complex inhibitors with potential application against immune and inflammatory disorders

Ulgheri, Fausta; Spanu, Pietro; Deligia, Francesco; Loriga, Giovanni; Fuggetta, Maria Pia; Haan, Iris de; Chandgudge, Ajay; Groves, Matthew R.; Dömling, Alexander

doi:10.1016/j.ejmech.2021.114002

Cited by 5 publications

(5 citation statements)

References 52 publications

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“…The multiple substitutable sites in the substrates of CIRs allow us to rapidly expand the scaffold library into a much bigger library. Compared with mono- or bi-component reactions, multi-component reactions provide more structurally diverse molecules in a single step 43 – 45 . This advantage benefits the diversity of compound libraries and increases the hit rate.…”

Section: Resultsmentioning

confidence: 99%

Carbenoid-involved reactions integrated with scaffold-based screening generates a Nav1.7 inhibitor

Shu,

Wang,

Guo

et al. 2024

Commun Chem

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The discovery of selective Nav1.7 inhibitors is a promising approach for developing anti-nociceptive drugs. In this study, we present a novel oxindole-based readily accessible library (OREAL), which is characterized by readily accessibility, unique chemical space, ideal drug-like properties, and structural diversity. We used a scaffold-based approach to screen the OREAL and discovered compound C4 as a potent Nav1.7 inhibitor. The bioactivity characterization of C4 reveals that it is a selective Nav1.7 inhibitor and effectively reverses Paclitaxel-induced neuropathic pain (PINP) in rodent models. Preliminary toxicology study shows C4 is negative to hERG. The consistent results of molecular docking and molecular simulations further support the reasonability of the in-silico screening and show the insight of the binding mode of C4. Our discovery of C4 paves the way for pushing the Nav1.7-based anti-nociceptive drugs forward to the clinic.

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Section: Resultsmentioning

confidence: 99%

Carbenoid-involved reactions integrated with scaffold-based screening generates a Nav1.7 inhibitor

Shu,

Wang,

Guo

et al. 2024

Commun Chem

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“…Caco-2 cells (0.1 × 10 6 cells/well) were seeded, as previously described for Model a, in the apical chamber of a 24-well transwell and cultured for 21 days. U937 cells (2 × 10 5 cells/well) were stimulated with 50 ng/mL of phorbol-12-myristate-13-acetate (PMA; Sigma-Aldrich, St. Louis, MO, USA) to differentiate into macrophage-like cells in a 24-well plate for 24 h, as described in the literature [ 48 ]. Then, the differentiated U937 macrophages (dU937) were stimulated with 1 µg/mL of LPS (Sigma-Aldrich) for 4 h and co-cultured with Caco-2 monolayer cells (week three) for 24 h.…”

Section: Methodsmentioning

confidence: 99%

Protective Effect of Limosilactobacillus fermentum ME-3 against the Increase in Paracellular Permeability Induced by Chemotherapy or Inflammatory Conditions in Caco-2 Cell Models

Gregorio

Serafino

Krasnowska

et al. 2023

IJMS

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Chemotherapy- or inflammation-induced increase in intestinal permeability represents a severe element in disease evolution in patients suffering from colorectal cancer and gut inflammatory conditions. Emerging data strongly support the gut microbiota’s role in preserving intestinal barrier integrity, whilst both chemotherapy and gut inflammation alter microbiota composition. Some probiotics might have a strong re-balancing effect on the gut microbiota, also positively affecting intestinal barrier integrity. In this study, we asked whether Limosilactobacillus fermentum ME-3 can prevent the intestinal paracellular permeability increase caused by the chemotherapeutic drug Irinotecan or by inflammatory stimuli, such as lipopolysaccharide (LPS). As an intestinal barrier model, we used a confluent and polarized Caco-2 cell monolayer and assessed the ME-3-induced effect on paracellular permeability by transepithelial electrical resistance (TEER) and fluorescent-dextran flux assays. The integrity of tight and adherens junctions was examined by confocal microscopy analysis. Transwell co-cultures of Caco-2 cells and U937-derived macrophages were used as models of LPS-induced intestinal inflammation to test the effect of ME-3 on release of the pro-inflammatory cytokines Tumor Necrosis Factor α, Interleukin-6, and Interleukin-8, was measured by ELISA. The results demonstrate that ME-3 prevents the IRI-induced increment in paracellular permeability, possibly by modulating the expression and localization of cell junction components. In addition, ME-3 inhibited both the increase in paracellular permeability and the release of pro-inflammatory cytokines in the co-culture model of LPS-induced inflammation. Our findings sustain the validity of L. fermentum ME-3 as a valuable therapeutic tool for preventing leaky gut syndrome, still currently without an available specific treatment.

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“…The tubulin polymerization result showed that 57a disrupts the microtubule network, arrests the cell cycle at the G2/M phase, and induces dose- and time-dependent apoptosis. Ulgheri and co-workers [ 61 ] reported designing and synthesizing a new class of active non-peptidomimetic and non-covalent caspase-1 inhibitors. Compound 58a was identified to inhibit IL-1β release in activated macrophages in the low µM range, which corroborates the activities observed for the known covalent inhibitors.…”

Section: Five-membered Heterocyclic Compoundsmentioning

confidence: 99%

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Ebenezer

Jordaan

Carena

et al. 2022

IJMS

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Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This has made them an indispensable motif in the drug discovery field. Heterocyclic compounds are usually classified according to the ring size, type, and the number of heteroatoms present in the ring. Among different heterocyclic ring systems, nitrogen heterocyclic compounds are more abundant in nature. They also have considerable pharmacological significance. This review highlights recent pioneering studies in the biological assessment of nitrogen-containing compounds, namely: triazoles, tetrazoles, imidazole/benzimidazoles, pyrimidines, and quinolines. It explores publications between April 2020 and February 2022 and will benefit researchers in medicinal chemistry and pharmacology. The present work is organized based on the size of the heterocyclic ring.

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Design, synthesis and biological evaluation of 1,5-disubstituted α-amino tetrazole derivatives as non-covalent inflammasome-caspase-1 complex inhibitors with potential application against immune and inflammatory disorders

Cited by 5 publications

References 52 publications

Carbenoid-involved reactions integrated with scaffold-based screening generates a Nav1.7 inhibitor

Carbenoid-involved reactions integrated with scaffold-based screening generates a Nav1.7 inhibitor

Protective Effect of Limosilactobacillus fermentum ME-3 against the Increase in Paracellular Permeability Induced by Chemotherapy or Inflammatory Conditions in Caco-2 Cell Models

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

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