Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies

Jitendra Kumar; Poonam Meena; Anju Singh; Ehtesham Jameel; Mudasir Maqbool; Mohammad Mobashir; Ashutosh Shandilya; Manisha Tiwari; Nasimul Hoda; B Jayaram

doi:10.1016/j.ejmech.2016.04.053

Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies

Eur J Med Chem. 2016 Aug 25:119:260-77. doi: 10.1016/j.ejmech.2016.04.053. Epub 2016 Apr 26.

Authors

Affiliations

¹ Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India.
² Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India.
³ Department of Chemistry, B. R. Ambedkar Bihar University, Muzaffarpur 842001, Bihar, India.
⁴ Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
⁵ Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India. Electronic address: mtiwari07@gmail.com.
⁶ Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi 110025, India. Electronic address: nhoda@jmi.ac.in.
⁷ Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India; Kusuma School of Biological Sciences, IIT Delhi, New Delhi 110016, India; Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi, New Delhi 110016, India.

PMID: 27227482
DOI: 10.1016/j.ejmech.2016.04.053

Abstract

In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.

Keywords: Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Molecular docking; Quinoline; Triazolopyrimidine.

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Amyloid beta-Peptides / chemistry
Animals
Antioxidants / chemical synthesis*
Antioxidants / pharmacokinetics
Antioxidants / pharmacology*
Antioxidants / therapeutic use
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Chemistry Techniques, Synthetic
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / pharmacokinetics
Cholinesterase Inhibitors / pharmacology*
Cholinesterase Inhibitors / therapeutic use
Drug Evaluation, Preclinical
Humans
Kinetics
Molecular Docking Simulation
Peptide Fragments / chemistry
Protein Aggregates / drug effects
Protein Conformation
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Pyrimidines / therapeutic use

Substances

Amyloid beta-Peptides
Antioxidants
Cholinesterase Inhibitors
Peptide Fragments
Protein Aggregates
Pyrimidines
amyloid beta-protein (1-42)
Acetylcholinesterase
Butyrylcholinesterase