Heterocyclic N-oxides - A Promising Class of Agents against Tuberculosis, Malaria and Neglected Tropical Diseases

Fernandes, Guilherme; Pavan, Aline Renata; Santos, Jean Leandro dos

doi:10.2174/1381612824666180417122625

Cited by 21 publications

(14 citation statements)

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“…Thus, the PCSK9-mediated degradation of LDLR increases LDL-C levels and promotes cardiovascular disease 42 . Interestingly, recent data have identified PCSK9 as a trigger for NAFLD 11 , 43 . Of note, the recent study shows that olanzapine treatment induces PCSK9-mediated dyslipidemia in patients with schizophrenia 44 .…”

Section: Discussionmentioning

confidence: 99%

“…As previously mentioned, PCSK9 is involved in the upregulation of triglyceride-rich lipoproteins and triglycerides through both LDLR-dependent and -independent pathways 13 . In addition, it has been demonstrated that high intrahepatic and circulating PCSK9 levels promote hepatic lipogenesis and lipid storage 11 , 43 , thus accelerating NAFLD pathogenesis. In this study, we demonstrated that metformin inhibits hepatic PCSK9 expression, in parallel to improving olanzapine-induced hepatic/hepatocyte steatosis in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, there was no difference in ratio of LC3B II/LC3B I and mTOR levels between metformin co-treatment with olanzapine and olanzapine mono-treatment group, which may exclude the action of autophagy on therapeutical effect of metformin. Thus, PCSK9 represents a potential therapeutic target for lipid and glucose metabolism disorders 43 caused by atypical antipsychotics.…”

Section: Discussionmentioning

confidence: 99%

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Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Zhu

Ding

Huang

et al. 2022

Sci Rep

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Studies have confirmed that olanzapine, the mainstay treatment for schizophrenia, triggers metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). However, the etiology of olanzapine-induced NAFLD is poorly understood. Proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in NAFLD pathogenesis, and metformin can significantly decrease circulating PCSK9. The purpose of this study was to investigate the role of PCSK9 and explore the therapeutic effect of metformin for olanzapine-associated NAFLD. Olanzapine significantly upregulated PCSK9 and promoted lipid accumulation in mouse livers and HepG2 and AML12 cells. Metformin ameliorated these pathological alterations. PCSK9 upstream regulator liver X receptor α (LXRα) was significantly upregulated in olanzapine-induced NAFLD. LXRα antagonist treatment and LXRα overexpression resulted in a decrease and increase of PCSK9, respectively. Hepatic lipogenesis-associated genes FAS and SCD1 were significantly upregulated in olanzapine-induced NAFLD mice and HepG2 cells overexpressing PCSK9, and genes related to lipid β-oxidation (SCAD and PPARα) were downregulated, while metformin reversed these changes. In addition, we found that LXRα overexpression compromised the effect of metformin on PCSK9 levels and intracellular lipid droplet formation. Taken together, our findings suggest that olanzapine enhances hepatic PCSK9 expression by upregulating LXRα, thereby increasing FAS and SCD1 expression as well as decreasing SCAD and PPARα, and promoting lipid accumulation, and, subsequently, NAFLD, which is ameliorated by metformin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Zhu

Ding

Huang

et al. 2022

Sci Rep

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“…A utilization of TEBAC as a phase transfer catalyst and Sc(OTf) 3 as a Lewis acid were crucial to increase the rate of the reduction and to avoid degradation of highly reactive diazonium salts 40 . A synthesized library of furoxan-based compounds represents an isosteric replacement of described drug candidates for the treatment of various neglected diseases including tuberculosis, leishmaniosis, schistosomiasis, and Chagas’ disease [ 83 , 84 , 85 , 86 ].…”

Section: Furoxansmentioning

confidence: 99%

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

Ферштат

Zhilin

2021

Molecules

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Nitric oxide (NO) is a key signaling molecule that acts in various physiological processes such as cellular metabolism, vasodilation and transmission of nerve impulses. A wide number of vascular diseases as well as various immune and neurodegenerative disorders were found to be directly associated with a disruption of NO production in living organisms. These issues justify a constant search of novel NO-donors with improved pharmacokinetic profiles and prolonged action. In a series of known structural classes capable of NO release, heterocyclic NO-donors are of special importance due to their increased hydrolytic stability and low toxicity. It is no wonder that synthetic and biochemical investigations of heterocyclic NO-donors have emerged significantly in recent years. In this review, we summarized recent advances in the synthesis, reactivity and biomedical applications of promising heterocyclic NO-donors (furoxans, sydnone imines, pyridazine dioxides, azasydnones). The synthetic potential of each heterocyclic system along with biochemical mechanisms of action are emphasized.

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“…The green chemistry methodologies available for their synthesis, which includes recyclable catalysts, microwave-assisted synthesis and water reactions, contribute to their attractiveness as drug development candidates [27]. Likewise, heterocyclic N -oxides have emerged as promising agents against several neglected and infectious diseases [28], and some quinoxaline derivatives have been reported as antihelminthic compounds against nematodes, cestodes, and trematodes [26,29].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin L Inhibitors with Activity against the Liver Fluke Identified From a Focus Library of Quinoxaline 1,4-di-N-Oxide Derivatives

et al. 2019

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Infections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-N-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against FhCL1 and FhCL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds C7, C17, C18, C19, C23, and C24 with an IC50 of less than 10 µM in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases.

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Heterocyclic N-oxides - A Promising Class of Agents against Tuberculosis, Malaria and Neglected Tropical Diseases

Cited by 21 publications

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Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

Cathepsin L Inhibitors with Activity against the Liver Fluke Identified From a Focus Library of Quinoxaline 1,4-di-N-Oxide Derivatives

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