Design and discovery of novel thiazole derivatives as potential MMP inhibitors to protect against acute lung injury in sepsis rats via attenuation of inflammation and apoptotic oxidative stress

Ge, Lingqing; Hu, Qiaozhen; Shi, Mengrao; Yang, Haojie; Zhu, Guoji

doi:10.1039/c7ra03511j

Cited by 15 publications

(8 citation statements)

References 31 publications

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“…It has also been reported that there were increases in the levels of caspase 3 and Bax/BcL 2 in the lungs. [40] The MDA level in liver tissue was elevated, whereas the GSH level decreased in the sepsis group compared with the controls. [31,39] These results are consistent with our sepsis model.…”

Section: Discussionmentioning

confidence: 83%

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Effects of Dapagliflozin on Experimental Sepsis Model in Rats

Kıngır¹

2018

Ulus Travma Acil Cerrahi Derg

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BACKGROUND: The aim of this study was to evaluate the possible protective effects of dapagliflozin in an experimental sepsis model in rats. METHODS: Saline (1 mL/kg, p.o.) or dapagliflozin (10 mg/kg, p.o.) was administered to Sprague-Dawley rats for 5 days prior to the surgical procedures. Under anesthesia, sepsis was induced by cecal ligation puncture, while sham control groups underwent laparotomy only. Blood urea nitrogen, creatinine, and glucose levels were measured in serum samples and the levels of malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), tumor necrosis factor alpha, interleukin 1 beta, caspase 8, and caspase 9 were determined in tissue samples (kidney, liver, and lung). Histological evaluation was also performed. RESULTS: The administration of dapagliflozin in a sepsis model reduced oxidative stress (MDA), increased antioxidant levels (GSH), and reduced inflammation (MPO) in the kidney (p<0.05). Dapagliflozin also decreased oxidative stress (MDA) in lung tissue and decreased inflammation (MPO) in lung and liver tissue (p<0.05). Caspase 8 and 9 levels in kidney, lung, and liver tissue were increased (p<0.05) in the dapagliflozin group compared with the sepsis group. According to the histopathological results, sepsis was moderately improved in renal tissue and slightly attenuated in lung and liver tissue with the administration of dapagliflozin. CONCLUSION: Dapagliflozin had a preventive effect on sepsis-induced kidney damage, but the protective effect was mild in lung and liver tissue in the present study.

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Section: Discussionmentioning

confidence: 83%

“…GSH levels were lower. [28,[36][37][38][39][40] In the histopathological evaluation, severe tissue damage was reported. [38] These results are also consistent with the findings we obtained in our sepsis model.…”

Section: Discussionmentioning

confidence: 99%

Effects of Dapagliflozin on Experimental Sepsis Model in Rats

Kıngır¹

2018

Ulus Travma Acil Cerrahi Derg

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“…Eur.J. 2019,25, www.chemeurj.org channel. Nevertheless, there are also inhibitors with another binding mode for the same enzyme that do not populate the S1'*p ocket, but protrudet ot he catalytic centerw ithouti nteracting with the zinc(II) ion.…”

Section: Non-zinc-binding Inhibitorsmentioning

confidence: 99%

“…[4] Since their discovery,M MPs have emerged as an intriguing target in pharmaceuticalr esearch. [5][6][7][8][9] Due to the involvement of members of the MMP family in am ultitude of severe diseases, such as cancer, [10][11][12][13][14][15][16] arthritis, [17,18] chronic obstructive pulmonary disease (COPD), [19][20][21] or sepsis, [22][23][24][25] great efforts weret aken to modulate MMP activity to possibly treat diseases in which MMP activity is out of balance. [26,27] Due to side effects evolving from al ack of selectivity and insufficient knowledge aboutt he relevance of the target family in pathological processes, no compound designed as an MMP inhibitor has reached the market so far,a nd clinicalt rials have failed.…”

Section: Introductionmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug‐discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small‐molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X‐ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure‐based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.

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“…Aminothiazole analogs have also been reported as ligands at adenosine receptors, 8 Anticonvulsants 9 and Thiazoles are also showed to exhibit numerous pharmacological activities 10 . This heterocyclic core is also reported in many natural products and pharmaceuticals.…”

Section: Quick Response Codementioning

confidence: 99%

Untitled

2018

IJPSR

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A quick one step, innovative approach for the Synthesis of 2aminothiazole derivatives from easily available thiourea and alkyl / aryl ketones with the help of Oxone and Iodobenzene reaction system has been developed in aqueous acetonitrile solution. The developed procedure is applicable to several types of substituted 2-aminothiazole derivatives to get the corresponding products. The developed methodology offers mild reaction condition, short reaction time, and moderate to admirable yields. This is one of the most simple and environmentally benign protocols for synthesis of 2aminothiazole derivatives. When reaction carried out in presence of oxone and Iodobenzene in aq. Acetonitrile solvent system there is formation of active Hypervalent iodine reagent in situ and that reagent is responsible for this conversion but, yield of reaction is less. We go in detailed in Hypervalent reagent study and got some literature in that researcher used catalytic KBr along with oxone and Iodobenzene and there is amplify in activity of Hypervalent iodine reagent because of catalytic amount of potassium bromide. So we decided to use catalytic amount of KBr along with oxone and Iodobenzene reagent and there is increase in yield of desirable product.

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Design and discovery of novel thiazole derivatives as potential MMP inhibitors to protect against acute lung injury in sepsis rats via attenuation of inflammation and apoptotic oxidative stress

Abstract: Effect of compound 26 on the expression of ICAM-1 and THP-1 cell adherence to activated A549 cells.

Cited by 15 publications

References 31 publications

Effects of Dapagliflozin on Experimental Sepsis Model in Rats

Effects of Dapagliflozin on Experimental Sepsis Model in Rats

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

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