Discovery of benzimidazole derivatives as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Zonghui Ma; Ling Jiang; Bingyan Li; Dailin Liang; Yu Feng; Li Liu; Cheng Jiang

doi:10.1016/j.bmc.2021.116352

Discovery of benzimidazole derivatives as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity

Bioorg Med Chem. 2021 Sep 15:46:116352. doi: 10.1016/j.bmc.2021.116352. Epub 2021 Aug 8.

Authors

Zonghui Ma¹, Ling Jiang², Bingyan Li³, Dailin Liang³, Yu Feng⁴, Li Liu⁵, Cheng Jiang⁶

Affiliations

¹ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China. Electronic address: zonghuima@126.com.
² Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
³ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China.
⁵ Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China. Electronic address: liulee@cpu.edu.cn.
⁶ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, China. Electronic address: jc@cpu.edu.cn.

PMID: 34403955
DOI: 10.1016/j.bmc.2021.116352

Abstract

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.

Keywords: Aldehyde dehydrogenase 1A1 (ALDH1A1); Benzimidazole; Glucose consumption; Inhibitors; Selectivity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aldehyde Dehydrogenase 1 Family / antagonists & inhibitors*
Aldehyde Dehydrogenase 1 Family / metabolism
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glucose / metabolism*
Humans
Molecular Structure
Retinal Dehydrogenase / antagonists & inhibitors*
Retinal Dehydrogenase / metabolism
Structure-Activity Relationship

Substances

Benzimidazoles
Enzyme Inhibitors
benzimidazole
Aldehyde Dehydrogenase 1 Family
ALDH1A1 protein, human
Retinal Dehydrogenase
Glucose