Design, synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors

Priti Jain; Pankaj K Wadhwa; Sinduri Gunapati; Hemant R Jadhav

doi:10.1016/j.bmc.2016.04.023

Design, synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors

Bioorg Med Chem. 2016 Jun 1;24(11):2567-2575. doi: 10.1016/j.bmc.2016.04.023. Epub 2016 Apr 12.

Authors

Priti Jain¹, Pankaj K Wadhwa², Sinduri Gunapati², Hemant R Jadhav³

Affiliations

¹ Computational Laboratory, Medicinal Chemistry Division, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India; Medicinal Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India.
² Medicinal Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India.
³ Computational Laboratory, Medicinal Chemistry Division, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India; Medicinal Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India. Electronic address: hemantrj@pilani.bits-pilani.ac.in.

PMID: 27102162
DOI: 10.1016/j.bmc.2016.04.023

Abstract

The identification of a series of sulfonyl-amino-acetamides as BACE-1 (β-secretase) inhibitors for the treatment of Alzheimer's disease is reported. The derivatives were designed based on the docking simulation study, synthesized and assessed for BACE-1 inhibition in vitro. The designed ligands revealed desired binding interactions with the catalytic aspartate dyad and occupance of S1 and S2' active site regions. These in silico results correlated well with in vitro activity. Out of 33 compounds synthesized, 12 compounds showed significant inhibition at 10μM concentration. The most active compound 2.17S had IC50 of 7.90μM against BACE-1, which was concomitant with results of in silico docking study.

Keywords: Alzheimer’s disease; BACE-1 inhibitors; Docking simulation; FRET assay; Sulfonyl-amino-acetamide.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Dose-Response Relationship, Drug
Drug Design*
Humans
Models, Molecular
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Protease Inhibitors
Small Molecule Libraries
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human