Potent immunosuppressive activity of a phosphodiesterase-4 inhibitor N-acylhydrazone in models of lipopolysaccharide-induced shock and delayed-type hypersensitivity reaction

Guimarães, Elisalva Teixeira; Santos, Tatiana B. dos; Silva, Dahara Keyse Carvalho; Meira, Cássio Santana; Moreira, Diogo Rodrigo Magalhães; Silva, Tiago Fernandes da; Salmon, Didier; Barreiro, Eliezer J.; Soares, Milena Botelho Pereira

doi:10.1016/j.intimp.2018.09.047

Cited by 6 publications

(16 citation statements)

References 40 publications

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“…All compounds were solubilized in dimethyl sulfoxide (DMSO) (PanReac, Barcelona, Spain) and for the use in the assays were diluted in cell culture medium. The final concentration of DMSO was <0.1% in all in vitro experiments and <5% in all in vivo experiments (Guimarães et al, 2018).…”

Section: Drugsmentioning

confidence: 89%

“…One-way analysis of variance and Newman-Keuls multiple comparison tests were employed by using Graph Pad Prism version 5.01 (Graph Pad Software, San Diego, CA, United States). Differences were considered significant when the values of p were <0.05 (Guimarães et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…These molecules can establish hydrogen bonds as an electron donor or acceptor and adopt several favorable conformational orientations due to the characteristics of their chemical structure (Fraga and Barreiro, 2006). Among these compounds, the methylated NAH derivative (E)-N′-(3,4-dimethoxybenzylidene)-4- methoxy-N-methylbenzohydrazide (LASSBio-1386) has been identified as a potent inhibitor of PDE-4 activity (Kümmerle et al, 2012;Guimarães et al, 2018). Given the high structural similarity shared between human and protozoan PDEs, this allowed us to hypothesize that LASSBio-1386 has activity against species from the Leishmania genus (Seebeck et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The N-acylhydrazone (NAH) is considered a privileged chemical structure used as a template for derivatization of multi-target drugs (Duarte et al, 2007). Compounds with this subunit showed antiparasitic, antimicrobial, and immunomodulatory actions (Kümmerle et al, 2012;Alencar et al, 2014;Guimarães et al, 2018;Thota et al, 2018). A series of new furoxanyl N-acylhydrazones presented antimicrobial and antiparasitic activities against Mycobacterium tuberculosis, Trypanosoma cruzi and Leishmania amazonensis (Hernández et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…LASSBio-1386, a NAH derivative (E)-N'-(3,4dimethoxybenzylidene)-4-methoxy-N-methylbenzohydrazide, presented a strong immunomodulatory action via NF-κB pathway inhibition and which could aid the inflammatory or immune-mediated diseases treatment (Guimarães et al, 2018). This compound promoted vascular hypertrophy in a pulmonary hypertension model (Alencar et al, 2014) and also showed potent inhibitory activity against human PDE-4 (HsPDE4) and significantly decreased TNF-α release by lipopolysaccharide (LPS)-activated human blood mononuclear cells (Kümmerle et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis

et al. 2020

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Leishmaniasis are group of neglected diseases with worldwide distribution that affect about 12 million people. The current treatment is limited and may cause severe adverse effects, and thus, the search for new drugs more effective and less toxic is relevant. We have previously investigated the immunomodulatory effects of LASSBio-1386, an N-acylhydrazone derivative. Here we investigated the in vitro and in vivo activity of LASSBio-1386 against L. amazonensis. LASSBio-1386 inhibited the proliferation of promastigotes of L. amazonensis (EC50 = 2.4 ± 0.48 µM), while presenting low cytotoxicity to macrophages (CC50 = 74.1 ± 2.9 µM). In vitro incubation with LASSBio-1386 reduced the percentage of Leishmania-infected macrophages and the number of intracellular parasites (EC50 = 9.42 ± 0.64 µM). Also, in vivo treatment of BALB/c mice infected with L. amazonensis resulted in a decrease of lesion size, parasitic load and caused histopathological alterations, when compared to vehicle-treated control. Moreover, LASSBio-1386 caused ultrastructural changes, arrested cell cycle in G0/G1 phase and did not alter the membrane mitochondrial potential of L. amazonensis. Aiming to its possible molecular interactions, we performed docking and molecular dynamics studies on Leishmania phosphodiesterase B1 (PDB code: 2R8Q) and LASSBio-1386. The computational analyses suggest that LASSBio-1386 acts against Leishmania through the modulation of leishmanial PDE activity. In conclusion, our results indicate that LASSBio-1386 is a promising candidate for the development of new leishmaniasis treatment.

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Section: Drugsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis

et al. 2020

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Modulation of the Acute Inflammatory Response Induced by the Escherichia coli Lipopolysaccharide through the Interaction of Pentoxifylline and Florfenicol in a Rabbit Model

et al. 2023

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Background: Experimental reports have demonstrated that florfenicol (FFC) exerts potent anti-inflammatory effects, improving survival in a murine endotoxemia model. Considering the anti-inflammatory and immunomodulatory properties of pentoxifylline (PTX) as an adjuvant to enhance the efficacy of antibiotics, the anti-inflammatory effects of the interaction FFC/PTX over the E. coli Lipopolysaccharide (LPS)-induced acute inflammatory response was evaluated in rabbits. Methods: Twenty-five clinically healthy New Zealand rabbits (3.8 ± 0.2 kg body weight: bw), were distributed into five experimental groups. Group 1 (control): treated with 1 mL/4 kg bw of 0.9% saline solution (SS) intravenously (IV). Group 2 (LPS): treated with an IV dose of 5 µg/kg of LPS. Group 3 (pentoxifylline (PTX) + LPS): treated with an oral dose of 30 mg/kg PTX, followed by an IV dose of 5 µg/kg of LPS 45 min after PTX. Group 4 (Florfenicol (FFC) + LPS): treated with an IM dose of 20 mg/kg of FFC, followed by an IV dose of 5 µg/kg of LPS 45 min after FFC administration. Group 5 (PTX + FFC + LPS): treated with an oral dose of 30 mg/kg of PTX, followed by an IM dose of 20 mg/kg of FFC, and, 45 min after an IV dose of 5 µg/kg of LPS was administered. The anti-inflammatory response was evaluated through changes in plasma levels of interleukins (TNF-α, IL-1β and IL-6), C-reactive protein (CRP), and body temperature. Results: It has been shown that each drug produced a partial inhibition over the LPS-induced increase in TNF-α, IL-1β, and CRP. When both drugs were co-administered, a synergistic inhibitory effect on the IL-1β and CRP plasma concentrations was observed, associated with a synergic antipyretic effect. However, the co-administration of PTX/FFC failed to modify the LPS-induced increase in the TNF-α plasma concentrations. Conclusions: We concluded that the combination of FFC and PTX in our LPS sepsis models demonstrates immunomodulatory effects. An apparent synergistic effect was observed for the IL-1β inhibition, which peaks at three hours and then decreases. At the same time, each drug alone was superior in reducing TNF-α levels, while the combination was inferior. However, the peak of TNF-α in this sepsis model was at 12 h. Therefore, in rabbits plasma IL-1β and TNF-α could be regulated independently, thus, further research is needed to explore the effects of this combination over a more prolonged period.

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Molecular Hybridization Strategy on the Design, Synthesis, and Structural Characterization of Ferrocene-N-acyl Hydrazones as Immunomodulatory Agents

et al. 2022

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Immunomodulatory agents are widely used for the treatment of immune-mediated diseases, but the range of side effects of the available drugs makes necessary the search for new immunomodulatory drugs. Here, we investigated the immunomodulatory activity of new ferrocenyl-N-acyl hydrazones derivatives (SintMed(141–156). The evaluated N-acyl hydrazones did not show cytotoxicity at the tested concentrations, presenting CC50 values greater than 50 µM. In addition, all ferrocenyl-N-acyl hydrazones modulated nitrite production in immortalized macrophages, showing inhibition values between 14.4% and 74.2%. By presenting a better activity profile, the ferrocenyl-N-acyl hydrazones SintMed149 and SintMed150 also had their cytotoxicity and anti-inflammatory effect evaluated in cultures of peritoneal macrophages. The molecules were not cytotoxic at any of the concentrations tested in peritoneal macrophages and were able to significantly reduce (p < 0.05) the production of nitrite, TNF-α, and IL-1β. Interestingly, both molecules significantly reduced the production of IL-2 and IFN-γ in cultured splenocytes activated with concanavalin A. Moreover, SintMed150 did not show signs of acute toxicity in animals treated with 50 or 100 mg/kg. Finally, we observed that ferrocenyl-N-acyl hydrazone SintMed150 at 100 mg/kg reduced the migration of neutrophils (44.6%) in an acute peritonitis model and increased animal survival by 20% in an LPS-induced endotoxic shock model. These findings suggest that such compounds have therapeutic potential to be used to treat diseases of inflammatory origin.

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Potent immunosuppressive activity of a phosphodiesterase-4 inhibitor N-acylhydrazone in models of lipopolysaccharide-induced shock and delayed-type hypersensitivity reaction

Cited by 6 publications

References 40 publications

In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis

In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis

Modulation of the Acute Inflammatory Response Induced by the Escherichia coli Lipopolysaccharide through the Interaction of Pentoxifylline and Florfenicol in a Rabbit Model

Molecular Hybridization Strategy on the Design, Synthesis, and Structural Characterization of Ferrocene-N-acyl Hydrazones as Immunomodulatory Agents

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