Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis

• Published in: European journal of medicinal chemistry 2017-09, Vol.138, p.729-737
• Main Authors: Azimi, Sara, Zonouzi, Afsaneh, Firuzi, Omidreza, Iraji, Aida, Saeedi, Mina, Mahdavi, Mohammad, Edraki, Najmeh
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Groebke–Blackburn–Bienayme reaction; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazopyridines; Isoindoles - chemistry; Isoindoles - pharmacology; Molecular docking; Molecular Structure; Phthalimide; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Structure-Activity Relationship; β-Secretase inhibitor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.06.040

Alzheimer's disease is characterized by chronic neurodegeneration leading to dementia. The main cause of neurodegeneration is considered to be the accumulation of amyloid-β. Inhibiting BACE1 is a well-studied approach to lower the burden of amyloid-β aggregates. We designed a series of imidazopyridines-based compounds bearing phthalimide moieties as inhibitors of BACE1. The compounds 8a-o were synthesized by the Groebke–Blackburn–Bienaymé three-component reaction of heteroaromatic amidines, aldehydes and isocyanides. Evaluating the BACE1 inhibitory effects of the synthesized compounds revealed that introducing an aminocyclohexyl moiety in the imidazopyridine core resulted in a significant improvement in its BACE1 inhibitory potential. In this regard, compound 8e was the most potent against BACE1 with an IC50 value of 2.84 (±0.95) μM. Molecular docking revealed that the nitrogen atom of imidazopyridines and the oxygen atom of the phenoxypropyl linker were involved in hydrogen bound interactions with Asp228 and Asp32 of BACE1 active site, respectively. The phthalimide moiety oriented toward the flap pocket and interacted with phe108, lle110, Trp115, Ile118 through van der Waal's and hydrophobic interactions. These findings demonstrate that imidazopyridines-based compounds bearing phthalimide moiety have the potential to decrease amyloid-β levels and ameliorate the symptoms of Alzheimer's disease. [Display omitted] •A novel class of imidazopyridine-phthalimide hybrids was rationally designed and synthesized as novel anti-Alzheimer agents.•All compounds were examined for their BACE1 inhibitory potential.•Compound 8e was the most potent against BACE1 with an IC50 value of 2.84 (±0.95) μM.•Molecular docking revealed the key binding interactions of 8e in BACE1 active site.