6287-83-8Relevant academic research and scientific papers
Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4-Oxadiazole Core: Hits Identification and Structure-Activity Relationship Study
Xu, Li-Li,Zhu, Jun-Feng,Xu, Xiao-Li,Zhu, Jie,Li,Xi, Mei-Yang,Jiang, Zheng-Yu,Zhang, Ming-Ye,Liu, Fang,Lu, Meng-Chen,Bao, Qi-Chao,Li, Qi,Zhang, Chao,Wei, Jin-Lian,Zhang, Xiao-Jin,Zhang, Lian-Shan,You, Qi-Dong,Sun, Hao-Peng
, p. 5419 - 5436 (2015)
Induction of phase II antioxidant enzymes by activation of Nrf2/ARE pathway has been recognized as a promising strategy for the regulation of oxidative stress-related diseases. Herein we report our effort on the discovery and optimization of Nrf2 activators with 1,2,4-oxadiazole core. Screening of an in-house collection containing 7500 compounds by ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecular similarity search by the combination of 2D fingerprint-based and 3D shape-based search was applied to virtually screening the Chemdiv collection. Three derivatives with the same core were identified to have better inductivity of Nrf2 than 1. The best hit 4 was selected as starting point for structurally optimization, leading to a much more potent derivative 32. It in vitro upregulated gene and protein level of Nrf2 as well as its downstream markers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammation in the in vivo LPS-challenged mouse model. Our results provide a new chemotype as Nrf2-ARE activators which deserve further optimization with the aim to obtain active anti-inflammatory agents through Nrf2-ARE pathway.
3-(1H-Benzo[d]imidazol-6-yl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (DDO7232), a novel potent Nrf2/ARE inducer, ameliorates DSS-induced murine colitis and protects NCM460 cells against oxidative stress via ERK1/2 phosphorylation
Li, Li,Xu, Li-Li,Liu, Tian,Wang, Lei,Wu, Yu-Feng,Li, Cui-Cui,Di, Bin,You, Qi-Dong,Jiang, Zheng-Yu
, (2018)
Ulcerative colitis (UC) is a common inflammatory bowel disease that can destroy the integrity of the colon and increase the risk of colorectal cancer. Oxidative stress is one of the critical pathogenic factors for UC, further impairing the entire affected colon. The Nrf2-ARE signaling pathway plays an important role in counteracting oxidative and electrophilic stress. Activation of the Nrf2- ARE pathway provides an indispensable defense mechanism for the treatment of UC. In this study, we identified a novel effective Nrf2 activator, DDO7232, which showed protective effects on NCM460 cells and therapeutic effects on DSS-induced colitis in mice. Mechanistic studies indicated that the Nrf2-ARE-inducing activity of DDO7232 was based on the activation of the ERK1/2 phosphorylation. The phosphorylation of Nrf2 Ser40 by p-ERK triggered the transport of Nrf2 into the nucleus and drove the expression of Nrf2-dependent antioxidant proteins. These results not only revealed the antioxidant mechanisms of DDO7232 but also provided an effective therapeutic option for the treatment of UC.
Visible-light-induced aerobic oxidative desulfurization of 2-mercaptobenzimidazolesviaa sulfinyl radical
Deng, Guo-Jun,Fu, Mei,Huang, Huawen,Ji, Xiaochen,Li, Yongtong
supporting information, p. 5594 - 5598 (2020/09/21)
A mild transition-metal-free non-toxic aerobic photoredox system was found to enable highly efficient desulfurization of 2-mercaptobenzimidazoles. This viable catalytic system includes Rose Bengal in a low catalyst loading as a photosensitizer and cheap, non-toxic NaCl in a catalytic amount as an additive, combined with an oxygen atmosphere. This protocol provides an important alternative access to a broad range of benzimidazole and deuterated benzimidazole products in generally high yields with good tolerance of various synthetically and pharmaceutically useful functionalities. The mechanistic studies reveal that both single electron transfer and energy transfer probably occur in the initial step and a sulfinyl radical intermediate is involved in the key desulfurization process.
K2S as Sulfur Source and DMSO as Carbon Source for the Synthesis of 2-Unsubstituted Benzothiazoles
Deng, Guobo,Kuang, Daizhi,Liang, Yun,Yang, Yuan,Yu, Jiangxi,Zhang, Fuxing,Zhu, Xiaoming
supporting information, p. 3789 - 3793 (2020/06/04)
We describe a three-component reaction of o-iodoanilines with K2S and DMSO that provides 2-unsubstituted benzothiazoles in moderate to good isolated yields with good functional group tolerance. Electron-rich aromatic amines and o-phenylenediamines instead of o-iodoanilines provided 2-unsubstituted benzothiazoles and 2-unsubstituted benzimidazoles with and without K2S under similar conditions. Notably, DMSO plays three vital roles: carbon source, solvent, and oxidant.
Synthesis method of ammonium acetate mediated benzimidazole compound
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Paragraph 0048-0050, (2020/11/23)
The invention discloses a synthesis method of a benzimidazole compound mediated by ammonium acetate. The synthesis method comprises the following steps: adding an o-phenylenediamine compound, dimethylsulfoxide, an additive 1 and an additive 2 into a reaction tube, carrying out a stirring reaction at 130-150 DEG C, cooling the reaction product to room temperature after the reaction is finished, and carrying out separation and purification on the product to obtain the benzimidazole compound. The invention develops a method for synthesizing a benzimidazole compound under the mediation of ammonium acetate by taking DMSO as a carbon source and an oxidant and an o-phenylenediamine compound as a substrate under the condition of no metal catalyst. The synthesis method does not need a metal catalyst, and the required carbon source and oxidant have the characteristics of low toxicity, low price, easiness in obtaining, stable performance and the like. The method has the advantages of easiness inoperation, few steps, mild reaction conditions, better functional group tolerance and the like, and provides a new valuable way for synthesizing benzimidazole compounds.
Transition-metal and oxidant-free approach for the synthesis of diverse N-heterocycles by TMSCl activation of isocyanides
Chen, Fen-Er,Dong, Lin,Li, Hongyan,Liu, Jinxin,Luo, Liangliang,Xiao, You-Cai,Zhou, Yuan
, p. 29257 - 29262 (2020/10/02)
A highly efficient TMSCl-mediated addition of N-nucleophiles to isocyanides has been achieved. This transition-metal and oxidant-free strategy has been applied to the construction of various N-heterocyles such as quinazolinone, benzimidazole and benzothiazole derivatives by the use of distinct amino-based binucleophiles. The notable feature of this protocol includes its mild reaction condition, broad functional group tolerance and excellent yield. This journal is
Facile access to: N-formyl imide as an N-formylating agent for the direct synthesis of N-formamides, benzimidazoles and quinazolinones
Huang, Hsin-Yi,Liang, Chien-Fu,Lin, Xiu-Yi,Yen, Shih-Yao
supporting information, p. 5726 - 5733 (2020/08/21)
N-Formamide synthesis using N-formyl imide with primary and secondary amines with catalytic amounts of p-toluenesulfonic acid monohydrate (TsOH·H2O) is described. This reaction is performed in water without the use of surfactants. Moreover, N-formyl imide is efficiently synthesized using acylamidines with TsOH·H2O in water. In addition, N-formyl imide was successfully used as a carbonyl source in the synthesis of benzimidazole and quinazolinone derivatives. Notable features of N-formylation of amines by using N-formyl imide include operational simplicity, oxidant- A nd metal-free conditions, structurally diverse products, and easy applicability to gram-scale operation.
Supported Rhodium (Rh@PS) Catalyzed Benzimidazoles Synthesis Using Ethanol/Methanol as C2H3/CH Source
Sharma, Saurabh,Sharma, Ajay,Yamini,Das, Pralay
supporting information, p. 67 - 72 (2018/12/05)
An effective and stable polystyrene supported rhodium (Rh@PS) nano-catalyst has been synthesized by following reduction-deposition approach and applied for the selective benzimidazoles synthesis from 1,2-phenylenediamines and ethanol/methanol as C2H3/CH source. The ethanol/methanol in the presence of trace amounts of aerobic oxygen under Rh@PS catalysed condition, first participated in oxidation of alcohol followed by consecutive condensation, cyclization and hydrogen elimination reactions with 1,2-phenylenediamine gave the desired products in good yields. The Rh@PS catalyst in a single system performed both oxidation and reduction reactions in a selective/specific manner and applied for large substrate scope. Easy recovery, handling, stability, recyclability of the catalyst and less chance of metal contamination with the products are the added advantages of the process. (Figure presented.).
A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity
Tran, Kim T.,Pallesen, Jakob S.,Solbak, Sara M.,Narayanan, Dilip,Baig, Amina,Zang, Jie,Aguayo-Orozco, Alejandro,Carmona, Rosa M. C.,Garcia, Anthony D.,Bach, Anders
supporting information, p. 8028 - 8052 (2019/10/11)
Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance - and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.
Microwave use of amidine compounds in the aqueous phase benzoate synthesis of benzimidazole compounds method
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Paragraph 0099, (2019/03/28)
The invention discloses a microwave the use of amidine compounds in the aqueous phase benzoate synthesis of benzimidazole compounds, in the aqueous phase under microwave conditions adding benzoic amidine compound under alkaline condition [...] into benzimidazole reaction, invention an environment-friendly, the operation is simple, cheap and safe, efficient process for preparing benzimidazole method. Compared with the prior art, this method not only can be applied to a large number of functional groups, the productive rate is high, few by-products, and the operation is simple, safe, low cost, environmental protection; .
