Design, synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors.
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.
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.
Priti
P
Jain
Medicinal Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India.
Pankaj K
PK
Wadhwa
Medicinal Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India.
Sinduri
S
Gunapati
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.
Hemant R
HR
Jadhav
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Alzheimer’s disease; BACE-1 inhibitors; Docking simulation; FRET assay; Sulfonyl-amino-acetamide