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  3. Rational design of novel diaryl ether-linked benzimidazole derivatives as potent and selective BACE1 inhibitors

Rational design of novel diaryl ether-linked benzimidazole derivatives as potent and selective BACE1 inhibitors

  • Biochem Biophys Res Commun. 2024 Feb 26:698:149538. doi: 10.1016/j.bbrc.2024.149538.
Tran Quang De 1,  Cuong Quoc Nguyen 2,  Quang Le Dang 3,  Nhu Y Nguyen Thi 4,  Nguyen Trong Tuan 5,  Dong Hoon Suh 6,  Jeonghyun Chu 6,  Sukumar Bepary 6,  Ge Hyeong Lee 6,  Nam Sook Kang 6,  Heeyeong Cho 6,  Woo Kyu Park 6,  Hee-Jong Lim 7
Affiliations

Affiliations

  • 1 Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 217 Gajeong-ro Yuseong-gu, Daejeon, 305-333, South Korea.
  • 2 Department of Chemistry, College of Natural Sciences, Can Tho University, Can Tho, 94000, Viet Nam; Analytical Techniques Lab (1.16-ATL), CTU High-tech Building, Can Tho University, Can Tho, 94000, Viet Nam. Electronic address: ncquoc99@gmail.com.
  • 3 Institute for Tropical Technology, Vietnam Academy of Science and Technology, Hanoi, 10072, Viet Nam; Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Hanoi, 10072, Viet Nam.
  • 4 Can Tho University of Technology, Can Tho, 94000, Viet Nam.
  • 5 Department of Chemistry, College of Natural Sciences, Can Tho University, Can Tho, 94000, Viet Nam.
  • 6 Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, P.O.Box 107, Yuseong-Gu, Daejeon, 305-600, South Korea.
  • 7 Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, P.O.Box 107, Yuseong-Gu, Daejeon, 305-600, South Korea. Electronic address: heejong@krict.re.kr.
PMID: 38271836 DOI: 10.1016/j.bbrc.2024.149538
Abstract

Due to the large size and high flexibility of the catalytic active site of BACE1 Enzyme, the development of nonpeptide inhibitors with optimal pharmacological properties is still highly demanding. In this work, we have discovered 2-aminobenzimidazole-containg ether scaffolds having potent and selective inhibitory potentials against BACE1 Enzyme. We have synthesized novel 29 compounds and optimization of aryl linker region resulted in highly potent BACE1 inhibitory activities with EC50 values of 0.05-2.71 μM. The aryloxy-phenyl analogs 20j showed the EC50 value as low as 0.07 μM in the Enzyme assay, whereas, the benzyloxyphenyl dervative 24b was comparatively less effective in the Enzyme assay. But interestingly the latter was more effective in the cell assay (EC50 value 1.2 μM). While comparing synthesized derivatives in the cell assay using PC12-APPSW cell, compound 27f appeared as the most potent BACE1 Inhibitor having EC50 value 0.7 μM. This scaffold also showed high selectivity over BACE2 Enzyme and Cathepsin D. Furthermore, the research findings were bolstered through the incorporation of molecular docking, molecular dynamics, and DFT studies. We firmly believe that these discoveries will pave the way for the development of a novel class of small-molecule selective BACE1 inhibitors.

Keywords

Alzheimer's disease; BACE1; Benzimidazole; Molecular docking; Non-peptide; β-secretase.

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