4-Substituted 2-amino-3,4-dihydroquinazolines with a 3-hairpin turn side chain as novel inhibitors of BACE-1

Ajit Dhananjay Jagtap; Nagendra B Kondekar; Pei-Yun Hung; Chen-En Hsieh; Chia-Ron Yang; Grace Shiahuy Chen; Ji-Wang Chern

doi:10.1016/j.bioorg.2019.103135

4-Substituted 2-amino-3,4-dihydroquinazolines with a 3-hairpin turn side chain as novel inhibitors of BACE-1

Bioorg Chem. 2020 Jan:95:103135. doi: 10.1016/j.bioorg.2019.103135. Epub 2019 Jul 22.

Authors

Ajit Dhananjay Jagtap¹, Nagendra B Kondekar², Pei-Yun Hung³, Chen-En Hsieh⁴, Chia-Ron Yang², Grace Shiahuy Chen⁵, Ji-Wang Chern⁶

Affiliations

¹ School of Pharmacy, College of Medicine and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan; AnnJi Pharmaceutical Co., Ltd., 18, Siyuan Street, Taipei 10087, Taiwan.
² School of Pharmacy, College of Medicine and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan.
³ AnnJi Pharmaceutical Co., Ltd., 18, Siyuan Street, Taipei 10087, Taiwan.
⁴ Department of Applied Chemistry, Providence University, No. 200, Section 7, Taiwan Boulevard, Taichung 43301, Taiwan.
⁵ Department of Applied Chemistry, Providence University, No. 200, Section 7, Taiwan Boulevard, Taichung 43301, Taiwan. Electronic address: grace@pu.edu.tw.
⁶ School of Pharmacy, College of Medicine and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan. Electronic address: jwchern@ntu.edu.tw.

PMID: 31923631
DOI: 10.1016/j.bioorg.2019.103135

Abstract

Herein, we report the identification, design, and synthesis of a series of 4-substituted 2-amino-3,4-dihydroquinazolines with hairpin turn side chains as novel inhibitors of BACE-1. The dihydroquinazoline derivatives were rationally designed by modifying the amide group and relocating the α -hydrophobic substituent on the hairpin turn side chain of lead compound 2 to the C4-position on the 3,4-dihydroquinazoline scaffold to facilitate interactions with the S₁, S₂ and S₁' subsites of BACE-1. Among these derivatives, two compounds exhibited potent BACE-1 inhibitory activity: 4-methyl-substituted (22a, BACE-1 CFA IC₅₀ = 0.38 μM; BACE-1 WCA IC₅₀ = 0.14 μM) and 4-cyclohexylmethyl-substituted (22b, BACE-1 CFA IC₅₀ = 0.49 μM; BACE-1 WCA IC₅₀ = 0.14 μM) 2-amino-3,4-dihydroquinazoline, each bearing a side chain of N-cyclohexyl-N-((1-methyl-1H-pyrazol-4-yl)methyl amide. The results suggest that the structural modifications maintain the hairpin turn topology similar to that of compound 2 and provide an additional interaction with the S₂ subsite.

Keywords: 2-amino-3; 4-dihydroquinazolines; Alzheimer’s disease; BACE-1; Non-peptidic aspartyl protease inhibitors; Structure-activity relationship.

Publication types

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

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Models, Molecular
Molecular Conformation
Quinazolines / chemical synthesis
Quinazolines / pharmacology
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Quinazolines
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human