scholarly journals Thiadiazoline- and Pyrazoline-Based Carboxamides and Carbothioamides: Synthesis and Inhibition against Nitric Oxide Synthase

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Fabio Arias ◽  
M. Encarnación Camacho ◽  
M. Dora Carrión ◽  
Meriem Chayah ◽  
Miguel Romero ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Aromatic Ring ◽  
Main Chain ◽  
Heterocyclic System ◽  
The Novel ◽  
Structure Activity ◽  
Inhibitory Activities ◽  
Oxide Synthase ◽  
Inos Inhibition

Two new families of pyrazoline and thiadiazoline heterocycles have been developed. Their inhibitory activities against two different isoforms of nitric oxide synthase (inducible and neuronal NOS) are reported. The novel derivatives were synthesized combining the arylthiadiazoline or arylpyrazoline skeleton and a carboxamide or carbothioamide moiety, used as starting material ethyl 2-nitrobenzoates or substituted nitrobenzaldehydes, respectively. The structure-activity relationships of final molecules are discussed in terms of the R1 radical effects in the aromatic ring, the Y atom in the heterocyclic system, the X heteroatom in the main chain, and the R2 substituent in the carboxamide or carbothioamide rest. In general, thiadiazolines (5a–e) inhibit preferentially the neuronal isoform; among them, 5a is the best nNOS inhibitor (74.11% at 1 mM, IC50 = 420 μM). In contrast, pyrazolines (6a–r) behave better as iNOS than nNOS inhibitors, 6m being the best molecule of this series (76.86% at 1 mM of iNOS inhibition, IC50 = 130 μM) and the most potent of all tested compounds.

Search for Potential Inducible Nitric Oxide Synthase Inhibitors with Favorable ADMET Profiles for the Therapy of Helicobacter pylori Infections

2020 ◽  
Vol 19 (30) ◽  
pp. 2795-2804 ◽  
Author(s):  
Ricardo Pereira Rodrigues ◽  
Juliana Santa Ardisson ◽  
Rita de Cássia Ribeiro Gonçalves ◽  
Tiago Branquinho Oliveira ◽  
Vinicius Barreto da Silva ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Helicobacter Pylori ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Crucial Role ◽  
Chemical Space ◽  
Target Selection ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

Background: Helicobacter pylori is a gram-negative bacterium related to chronic gastritis, peptic ulcer and gastric carcinoma. During its infection process, promotes excessive inflammatory response, increasing the release of reactive species and inducing the production of pro-inflammatory mediators. Inducible Nitric Oxide Synthase (iNOS) plays a crucial role in the gastric carcinogenesis process and a key mediator of inflammation and host defense systems, which is expressed in macrophages induced by inflammatory stimuli. In chronic diseases such as Helicobacter pylori infections, the overproduction of NO due to the prolonged induction of iNOS is of major concern. Objective: In this sense, the search for potential iNOS inhibitors is a valuable strategy in the overall process of Helicobacter pylori pathogeny. Method: In silico techniques were applied in the search of interesting compounds against Inducible Nitric Oxide Synthase enzyme in a chemical space of natural products and derivatives from the Analyticon Discovery databases. Results: The five compounds with the best iNOS inhibition profile were selected for activity and toxicity predictions. Compound 9 (CAS 88198-99-6) displayed significant potential for iNOS inhibition, forming hydrogen bonds with residues from the active site and an ionic interaction with heme. This compound also displayed good bioavailability and absence of toxicity/or from its probable metabolites. Conclusion: The top-ranked compounds from the virtual screening workflow show promising results regarding the iNOS inhibition profile. The results evidenced the importance of the ionic bonding during docking selection, playing a crucial role in binding and positioning during ligand-target selection for iNOS.

Effects of chronic inhibition of inducible nitric oxide synthase in hyperthyroid rats

2005 ◽  
Vol 288 (6) ◽  
pp. E1252-E1257 ◽  
Author(s):  
Isabel Rodríguez-Gómez ◽  
Rosemary Wangensteen ◽  
Juan Manuel Moreno ◽  
Virginia Chamorro ◽  
Antonio Osuna ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Control Group ◽  
Hemodynamic Variable ◽  
Male Wistar Rats ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

We hypothesized that nitric oxide generated by inducible nitric oxide synthase (iNOS) may contribute to the homeostatic role of this agent in hyperthyroidism and may, therefore, participate in long-term control of blood pressure (BP). The effects of chronic iNOS inhibition by oral aminoguanidine (AG) administration on BP and morphological and renal variables in hyperthyroid rats were analyzed. The following four groups ( n = 8 each) of male Wistar rats were used: control group and groups treated with AG (50 mg·kg−1·day−1, via drinking water), thyroxine (T4, 50 μg·rat−1·day−1), or AG + T4. All treatments were maintained for 3 wk. Tail systolic BP and heart rate (HR) were recorded weekly. Finally, we measured BP (mmHg) and HR in conscious rats and morphological, plasma, and renal variables. T4 administration produced a small BP (125 ± 2, P < 0.05) increase vs. control (115 ± 2) rats. AG administration to normal rats did not modify BP (109 ± 3) or any other hemodynamic variable. However, coadministration of T4 and AG produced a marked increase in BP (140 ± 3, P < 0.01 vs. T4). Pulse pressure and HR were increased in both T4- and T4 + AG -treated groups without differences between them. Plasma NOx (μmol/l) were increased in the T4 group (10.02 ± 0.15, P < 0.05 vs. controls 6.1 ± 0.10), and AG reduced this variable in T4-treated rats (6.81 ± 0.14, P < 0.05 vs. T4) but not in normal rats (5.78 ± 0.20). Renal and ventricular hypertrophy and proteinuria of hyperthyroid rats were unaffected by AG treatment. In conclusion, the results of the present paper indicate that iNOS activity may counterbalance the prohypertensive effects of T4.

Diyabetik sıçanların karaciğer ve böbrekleri üzerinde Caralluma tuberculata’nın hipoglisemik ve hipolipidemik etkisi ve güvenliği / Liquidambar orientalis Mill. reçine ekstraktlarının antioksidan, sitotoksik ve iNOS aktiviteleri

2016 ◽  
Vol 41 (3) ◽  
Author(s):  
Ayşe Nalbantsoy ◽  
Mert Karış ◽  
Leyla Karakaya ◽  
Yurdanur Akgül
Keyword(s):  
Nitric Oxide ◽  
Antioxidant Activity ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
No Production ◽  
Raw 264.7 ◽  
Water Extracts ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

AbstractObjective: The aim of this study is to investigate the in vitro cytotoxicity and iNOS (inducible nitric oxide synthase) inhibitory, and antioxidant activity in order to assess the traditional usage of Liquidambar orientalis Mill resin extract.Methods: Different solvent extracts of Liquidambar orientalis Mill resin were prepared. The cytotoxicity of extracts was determined using MTT (3-(4,5-dimethyl-2-thiazolyl)- 2,5-diphenyl-2H-tetrazoliumbromide) assay. HeLa (Human cervix adenocarcinoma), A-549 (Human alveolar adenocarcinoma), MCF-7 (Human breast adenocarcinoma), CaCo-2 (Human colon colorectal adenocarcinoma), mPANC96 (Human pancreas adenocarcinoma), PC-3 (Human prostate adenocarcinoma), U87MG (Human glioblastoma- astrocytoma) and as a normal cell line HEK293 (Human embryonic kidney cells) and Vero (African green monkey kidney epithelial cells) were used for testing cytotoxicity. RAW 264.7 (murine macrophage cell lines) was used to determine the inhibition levels of inducible nitric oxide synthase (iNOS). HL-60 (human acute myeloid leukemia) was used to determine antioxidant activity as DCF production per cent.Results: Hexane, dichloromethane, methanol and water extracts were prepared, and their iNOS inhibitory, cytotoxic and antioxidant activity were investigated. The estimated IC50 values of extracts varied from 6.68 to 48.90 μg/ ml after treatment with different doses of extracts for 48 h. Inhibition of the hexane, dichloromethane, methanol, and water extracts on LPS-induced NO production in RAW 264.7 macrophage were showed that the all extracts inhibited NO production in activated RAW 264.7 cells, except methanol extract. Hexane, dichloromethane and methanol extracts inhibited NO production with ICConclusion: This study is the first report showing the potential of Liquidambar orientalis Mill resin extracts for cytotoxicity, iNOS inhibition and the antioxidant activity as an alternative therapeutic approach for traditional uses. The results demonstrated that Liquidambar orientalis dichloromethane resin extracts showed strongest cytotoxic effect while all extracts except methanolic extracts exhibited moderate iNOS inhibition. All extracts other than hexane have a potent antioxidant effect in the cellular-based assay. In conclusion, further studies should focus on the purification of the active components of this extracts and to investigate the possible mode of action to obtain a better understanding of their potential use as cytotoxic, anti-inflammatory and antioxidant agents.

scholarly journals Inducible Nitric Oxide Synthase Deficiency in Myeloid Cells Does Not Prevent Diet-Induced Insulin Resistance

2010 ◽  
Vol 24 (7) ◽  
pp. 1413-1422 ◽  
Author(s):  
Min Lu ◽  
PingPing Li ◽  
Jan Pferdekamper ◽  
WuQiang Fan ◽  
Maziyar Saberi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Myeloid Cells ◽  
Mixed Effect ◽  
Insulin Resistant ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

Abstract Recent findings denote an important contribution of macrophage inflammatory pathways in causing obesity-related insulin resistance. Inducible nitric oxide synthase (iNOS) is activated in proinflammatory macrophages and modestly elevated in insulin-responsive tissues. Although the benefits of systemic iNOS inhibition in insulin-resistant models have been demonstrated, the role of macrophage iNOS in metabolic disorders is not clear. In the current work, we used bone marrow transplantation (BMT) to generate mice with myeloid iNOS deficiency [iNOS BMT knockout (KO)]. Interestingly, disruption of iNOS in myeloid cells did not protect mice from high-fat diet-induced obesity and insulin resistance. When mice were treated with the iNOS inhibitor, N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL), we observed a significant and comparable improvement of glucose homeostasis and insulin sensitivity in both wild-type and iNOS BMT KO mice. We further demonstrated that absence of iNOS in primary macrophages did not affect acute TLR4 signaling pathways and had only a modest and mixed effect on inflammatory gene expression. With respect to TNFα treatment, iNOS KO macrophages showed, if anything, a greater inflammatory response. In summary, we conclude that iNOS inhibition in tissues other than myeloid cells is responsible for the beneficial effects in obesity/insulin resistance.

THE EFFECT OF INDUCIBLE NITRIC OXIDE SYNTHASE (iNOS) INHIBITION ON SMOKE INHALATION INJURY IN SHEEP

Shock ◽  
2000 ◽  
Vol 13 (4) ◽  
pp. 261-266 ◽  
Author(s):  
Kazutaka Soejima ◽  
Roy McGuire ◽  
Ned Snyder ◽  
Tatsuo Uchida ◽  
Csaba Szabó ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Inhalation Injury ◽  
Smoke Inhalation ◽  
Smoke Inhalation Injury ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

scholarly journals Identification of Hypoglycemia-dependent Endothelial Nitric Oxide Synthase O-GlcNAcylation Sites and Regulation of O-GlcNAcylation and Nitric Oxide Production by Hypoglycemia

2020 ◽  
Author(s):  
an he ◽  
Shupeng Hu ◽  
Qiangzhong Pi ◽  
Yongzheng Guo ◽  
Yang Long ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Immunoblot Analysis ◽  
Serine Phosphorylation ◽  
The Novel ◽  
Post Translational Modification ◽  
Enos Activity ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Abstract BackgroundO-GlcNAcylation, an energy-sensitive post-translational modification, plays a major role in endothelial nitric oxide synthase (eNOS) activity regulation. However, the effect of hypoglycemia on eNOS O-GlcNAcylation and whether eNOS exists the novel O-GlcNAcylation sites under hypoglycemia is unknown. Hence, we endeavored to determine the effects of hypoglycemia on eNOS O-GlcNAcylation and the novel O-GlcNAcylation sites of eNOS.MethodBovine aortic endothelial cells (BAECs) and Sprague-Dawley rats were treated by hypoglycemia, and using immunoblotting to measure their eNOS O-GlcNAcylation. eNOS and transfected eNOS were purified by pull-down assay and immunoprecipitation respectively. Novel O-GlcNAcylation sites of eNOS were predicted by HPLC-MS and MS/MS Ion, and determined by immunoblotting. eNOS activity were detected by Elisa and isotope labelling method. ResultsIn BAECs and rats` thoracic aorta, hypoglycemia-associated activation of eNOS was accompanied by an increase in O-GlcNAcylation and had no effect on O-linked serine phosphorylation at residue 1179/1177. Changes in this post-translational modification were associated with increased O-GlcNAc transferase (OGT) activity, and were reversed by AMPK knockdown. Immunoblot analysis of cells expressing His-tagged wild-type human eNOS and human eNOS carrying a mutation at the Ser1177 phosphorylation site confirmed the increase in O-GlcNAcylation in response to hypoglycemia. The observed increase in O-GlcNAcylation indicated that eNOS contains novel O-GlcNAcylation sites that are activated by hypoglycemia. Immunoblot analysis of cells expressing His-tagged human eNOS carrying a mutation at Ser738 and Ser867 confirmed the increase in O-GlcNAcylation in response to hypoglycemia. Contrastingly, in His-tagged human eNOS carrying a mutation at Thr866, O-GlcNAcylation was unaffected by hypoglycemia. Differences among culture conditions were identified using two-way analysis of variance (ANOVA), one-way ANOVA, or unpaired Student’s t-test. ConclusionsHypoglycemia increases eNOS O-GlcNAcylation and activity, potentially via AMPK-OGT pathway, thereby showing the Thr866 as a novel O-GlcNAcylation site involved in hypoglycemia-mediated eNOS activation.

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