<abstract xmlns="http://www.w3.org/1999/xhtml">
The current work was conducted to elucidate the pharmacological effect of pyrazole-conjugated imidazo[1,2-<italic>a</italic>]pyrazine derivatives against acute lung injury in rats in sepsis and their mechanism of action. Various pyrazole-conjugated imidazo[1,2-<italic>a</italic>]-pyrazine derivatives have been synthesized in a straightforward synthetic route. They exhibited a diverse range of inhibitory activity against NF-ĸB with <italic>IC</italic>50 ranging from 1 to 94 µmol L–1. Among them, compound <bold>3h</bold> [(4-(4-((4-hydroxyphenyl)sulfonyl) phenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1<italic>H</italic>-pyrazol-1-yl) (8-(methylamino)imidazo[1,2-<italic>a</italic>]pyrazin-2-yl)methanone] was identified as the most potent NF-κB inhibitor with <italic>IC</italic>50 of 1.02 µmol L–1. None of the synthesized compounds was found cytotoxic to normal cell-line MCF-12A. The pharmacological activity of the most potent NF-ĸB inhibitor <bold>3h</bold> was also investigated in cecal ligation and puncture (CLP)-induced sepsis injury of the lung in rats. Compound <bold>3h</bold> was administered to rats after induc tion of lung sepsis, and various biochemical parameters were measured. Results suggested that compound <bold>3h</bold> significantly reduced lung inflammation and membrane permeability, as evidenced by H&amp;E staining of lung tissues. It substantially reduced the generation of pro-inflammatory cytokines (TNF-α, IL-1B, IL-6) and oxidative stress (MPO, MDA, SOD). It showed attenuation of NF-ĸB and apoptosis in Western blot and annexin--PI assay, resp. Compound <bold>3h</bold> also reduced the production of bronchoalveolar lavage fluid from the lung and provided a protective effect against lung injury. Our study showed the pharmacological significance of pyrazole-conjugated imidazo[1,2-<italic>a</italic>] pyrazine derivative <bold>3h</bold> against acute lung injury in sepsis rats.
</abstract>

The current work was conducted to elucidate the pharmacological effect of pyrazole-conjugated imidazo[1,2-a]pyrazine derivatives against acute lung injury in rats in sepsis and their mechanism of action. Various pyrazole-conjugated imidazo[1,2-a]-pyrazine derivatives have been synthesized in a straightforward synthetic route. They exhibited a diverse range of inhibitory activity against NF-ĸB with IC50 ranging from 1 to 94 µmol L–1. Among them, compound 3h [(4-(4-((4-hydroxyphenyl)sulfonyl) phenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl) (8-(methylamino)imidazo[1,2-a]pyrazin-2-yl)methanone] was identified as the most potent NF-κB inhibitor with IC50 of 1.02 µmol L–1. None of the synthesized compounds was found cytotoxic to normal cell-line MCF-12A. The pharmacological activity of the most potent NF-ĸB inhibitor 3h was also investigated in cecal ligation and puncture (CLP)-induced sepsis injury of the lung in rats. Compound 3h was administered to rats after induc tion of lung sepsis, and various biochemical parameters were measured. Results suggested that compound 3h significantly reduced lung inflammation and membrane permeability, as evidenced by H&E staining of lung tissues. It substantially reduced the generation of pro-inflammatory cytokines (TNF-α, IL-1B, IL-6) and oxidative stress (MPO, MDA, SOD). It showed attenuation of NF-ĸB and apoptosis in Western blot and annexin--PI assay, resp. Compound 3h also reduced the production of bronchoalveolar lavage fluid from the lung and provided a protective effect against lung injury. Our study showed the pharmacological significance of pyrazole-conjugated imidazo[1,2-a] pyrazine derivative 3h against acute lung injury in sepsis rats.

Synthesis and protective effect of pyrazole conjugated imidazo[1,2-<italic>a</italic>]pyrazine derivatives against acute lung injury in sepsis rats <italic>via</italic> attenuation of NF-κB, oxidative stress, and apoptosis

Henan Province Hospital of TCMThe Second Affiliated Hospital of Henan University of TCM

Acta Pharmaceutica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Synthesis and protective effect of pyrazole conjugated imidazo[1,2-]pyrazine derivatives against acute lung injury in sepsis rats  attenuation of NF-κB, oxidative stress, and apoptosis

The current work was conducted to elucidate the pharmacological effect of pyrazole-conjugated imidazo[1,2-a]pyrazine derivatives against acute lung injury in...

Synthesis and protective effect of pyrazole conjugated imidazo[1,2-a]pyrazine derivatives against acute lung injury in sepsis rats via attenuation of NF-κB, oxidative stress, and apoptosis

Data publikacji: 14 wrz 2023

Zakres stron: 341 - 362

Przyjęty: 14 cze 2023

DOI: https://doi.org/10.2478/acph-2023-0031

Słowa kluczowe
pyrazole-conjugated imidazo[1, 2-]pyrazine derivatives, synthesis, rats, sepsis, NF-ĸB, inflammation, oxidative stress, apoptosis

© 2023 Binbin Zang et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Synthesis and protective effect of pyrazole conjugated imidazo[1,2-a]pyrazine derivatives against acute lung injury in sepsis rats via attenuation of NF-κB, oxidative stress, and apoptosis

Data publikacji: 14 wrz 2023

Zakres stron: 341 - 362

Przyjęty: 14 cze 2023

DOI: https://doi.org/10.2478/acph-2023-0031

Słowa kluczowepyrazole-conjugated imidazo[1, 2-]pyrazine derivatives, synthesis, rats, sepsis, NF-ĸB, inflammation, oxidative stress, apoptosis

© 2023 Binbin Zang et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Słowa kluczowe
pyrazole-conjugated imidazo[1, 2-]pyrazine derivatives, synthesis, rats, sepsis, NF-ĸB, inflammation, oxidative stress, apoptosis