Rational design, synthesis and in vitro evaluation of allylidene hydrazinecarboximidamide derivatives as BACE-1 inhibitors

Priti Jain; Pankaj K Wadhwa; Shilpa Rohilla; Hemant R Jadhav

doi:10.1016/j.bmcl.2015.11.044

Rational design, synthesis and in vitro evaluation of allylidene hydrazinecarboximidamide derivatives as BACE-1 inhibitors

Bioorg Med Chem Lett. 2016 Jan 1;26(1):33-7. doi: 10.1016/j.bmcl.2015.11.044. Epub 2015 Nov 14.

Authors

Priti Jain¹, Pankaj K Wadhwa², Shilpa Rohilla², Hemant R Jadhav³

Affiliations

¹ Computational Chemistry Laboratory, 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 Chemistry Laboratory, 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: 26614409
DOI: 10.1016/j.bmcl.2015.11.044

Abstract

BACE-1 (β-secretase) is considered to be one of the promising targets for treatment of Alzheimer's disease as it catalyzes the rate limiting step of Aβ-42 production. Herein, we report a novel class of allylidene hydrazinecarboximidamide derivatives as moderately potent BACE-1 inhibitors, having aminoguanidine substitution on allyl linker with two aromatic groups on either side. A library of derivatives was designed based on the docking studies, synthesized and evaluated for BACE-1 inhibition in vitro. The designed ligands displayed interactions with the catalytic aspartate dyad through guanidinium functionality. Further, the aromatic rings placed on either side of the linker occupied S1 and S3 active site regions contributing to the activity. These ligands were also predicted to follow Lipinski rule and cross blood brain barrier. Compound 2.21, having high docking score, was found to be most active with IC50 of 6.423μM indicating good correlation with docking prediction.

Keywords: Allylidene hydrazinecarboximidamide; Alzheimer’s disease; BACE-1; Docking simulation.

Publication types

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

MeSH terms

Allyl Compounds / chemical synthesis
Allyl Compounds / chemistry
Allyl Compounds / pharmacology*
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 Design*
Humans
Hydrazines / chemical synthesis
Hydrazines / chemistry
Hydrazines / pharmacology*
Molecular Docking Simulation
Molecular Structure
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Allyl Compounds
Hydrazines
Protease Inhibitors
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human