380568-64-9Relevant articles and documents
Discovery of benzimidazole derivatives as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity
Ma, Zonghui,Jiang, Ling,Li, Bingyan,Liang, Dailin,Feng, Yu,Liu, Li,Jiang, Cheng
, (2021/08/17)
Aldehyde dehydrogenase 1A1 (ALDH1A1) plays vital physiological and toxicological functions in many areas, such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of ALDH1A1 has been disclosed to play an important role in obesity, diabetes and other diseases, indicating the potential need for the identification and development of small molecule ALDH1A1 inhibitors. Herein, a series of benzimidazole derivatives was designed, synthesized and evaluated. Among them, compounds 21, 27, 29, 61 and 65 exhibited excellent inhibitory activity against ALDH1A1 with IC50 values in the low micromolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Moreover, an in vitro study demonstrated that all five compounds effectively improved glucose consumption in HepG2 cells, of which, 61 and 65 at 10 μM produced nearly equal glucose consumption with positive control Metformin (Met) at 1 mM. Furthermore, 61 and 65 showed desirable metabolic stability in human liver microsomes. All these results suggest that 61 and 65 are suitable for further studies.
Benzimidazole derivative, preparation method and application thereof
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Paragraph 0043-0047, (2020/07/21)
The invention discloses a benzimidazole derivative shown as general formula I or pharmaceutically acceptable salts thereof, a preparation method and application thereof as a selective retinal dehydrogenase inhibitor. Specifically, R1 is selected from C1-C8 alkyl, C2-C8 alkenyl, cycloalkyl methyl or benzyl; the cycloalkyl is a 3-6-membered cycloalkyl; the benzyl can optionally be substituted by oneor more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy, or CF3. Compared with the prior art, the invention discloses abenzimidazole derivative and pharmaceutically acceptable salts thereof with a selective inhibition effect on retinal dehydrogenase (ALDH1A1). And pharmacological experiments prove that the compounds have a remarkable inhibition effect on ALDH1A1 and particularly can be used as diabetes treatment drugs.
Design, synthesis, and biological evaluation of novel thiazolidinediones as PPAR3/FFAR1 dual agonists
Darwish, Khaled M.,Salama, Ismail,Mostafa, Samia,Gomaa, Mohamed S.,Helal, Mohamed A.
, p. 157 - 172 (2016/01/16)
Diabetes mellitus is a chronic metabolic disorder that affects more than 180 million people worldwide. Peroxisome proliferator activated receptors (PPARs) are a group of nuclear receptors that have been targeted by the thiazolidinedione (TZD) class of compounds for the management of type II diabetes. PPAR3 is known to regulate adipogenesis and glucose metabolism. Another emerging target for the design of antidiabetic agents is the free fatty acid receptor 1 (FFAR1), previously known as GPR40. Agonists of this receptor were found to enhance insulin secretion in diabetic patients. It has been reported that some thiazolidinediones (TZDs) activate FFAR1 with micromolar potency. In this study, based on docking studies into the crystal structure of PPAR3 and a homology model of FFAR1, nineteen compounds were designed, synthesized, and biologically tested for agonistic activity on both receptors. Nine compounds showed promising dual activity, with two compounds, 11a and 5b, having affinities in the low micromolar range on both targets. These molecules represent the first antidiabetic agents that could act as insulin sensitizers as well as insulin secretagogues.
Structure-Activity Relationship and Pharmacokinetic Studies of 1,5-Diheteroarylpenta-1,4-dien-3-ones: A Class of Promising Curcumin-Based Anticancer Agents
Wang, Rubing,Chen, Chengsheng,Zhang, Xiaojie,Zhang, Changde,Zhong, Qiu,Chen, Guanglin,Zhang, Qiang,Zheng, Shilong,Wang, Guangdi,Chen, Qiao-Hong
, p. 4713 - 4726 (2015/06/25)
Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner-Wadsworth-Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure-activity data acquired from the study validated (1E,4E)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1H-imidazol-2-yl, ortho pyridyl, 1-alkyl-1H-benzo[d]imidazole-2-yl, 4-bromo-1-methyl-1H-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1E,4E)-1,5-Bis(2-methyl-4-(trifluoromethyl)thiazol-5-yl)penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles. (Chemical Equation Presented).
