TY - JOUR
T1 - Discovery of benzimidazole derivatives as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity
AU - Ma, Zonghui
AU - Jiang, Ling
AU - Li, Bingyan
AU - Liang, Dailin
AU - Feng, Yu
AU - Liu, Li
AU - Jiang, Cheng
N1 - Funding Information:
This work was supported by Natural Science Foundation of China (No. 82073685 and 81673505 ); “Qinglan project” of Jiangsu province; Excellent Science and Technology Innovation Team Projects of Jiangsu Province Universities in 2017 and “Double First-Class” university project (No. CPU2018GY22).
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/9/15
Y1 - 2021/9/15
N2 - 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.
AB - 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.
KW - Aldehyde dehydrogenase 1A1 (ALDH1A1)
KW - Benzimidazole
KW - Glucose consumption
KW - Inhibitors
KW - Selectivity
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U2 - 10.1016/j.bmc.2021.116352
DO - 10.1016/j.bmc.2021.116352
M3 - Article
C2 - 34403955
AN - SCOPUS:85112422220
SN - 0968-0896
VL - 46
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
M1 - 116352
ER -