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Eur J Med Chem. 2017 Aug 18;136:36-51. doi: 10.1016/j.ejmech.2017.04.064. Epub 2017 Apr 24.

Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents.

Author information

1
Department of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, 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
Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India. Electronic address: mtiwari07@gmail.com.
5
Department of Chemistry, Jamia Millia Islamia (Central University), Jamia Nagar, New Delhi 110025, India. Electronic address: nhoda@jmi.ac.in.
6
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.

Abstract

In our endeavor towards the development of potent multitarget ligands for the treatment of Alzheimer's disease, a series of triazine-triazolopyrimidine hybrids were designed, synthesized and characterized by various spectral techniques. Docking and scoring techniques were used to design the inhibitors and to display their interaction with key residues of active site. Organic synthesis relied upon convergent synthetic routes were mono and di-substituted triazines were connected with triazolopyrimidine using piperazine as a linker. In total, seventeen compounds were synthesized in which the di-substituted triazine-triazolopyrimidine derivatives 9a-d showed better acetylcholinesterase (AChE) inhibitory activity than the corresponding tri-substituted triazine-triazolopyrimidine derivatives 10a-f. Out of the disubstituted triazine-triazolopyrimidine based compounds, 9a and 9b showed encouraging inhibitory activity on AChE with IC50 values 0.065 and 0.092 μM, respectively. Interestingly, 9a and 9b also demonstrated good inhibition selectivity towards AChE over BuChE by ∼28 folds. Furthermore, kinetic analysis and molecular modeling studies showed that 9a and 9b target both catalytic active site as well as peripheral anionic site of AChE. In addition, these derivatives effectively modulated Aβ self-aggregation as investigated through CD spectroscopy, ThT fluorescence assay and electron microscopy. Besides, these compounds exhibited potential antioxidants (2.15 and 2.91 trolox equivalent by ORAC assay) and metal chelating properties. In silico ADMET profiling highlighted that, these novel triazine derivatives have appropriate drug like properties and possess very low toxic effects in the primarily pharmacokinetic study. Overall, the multitarget profile exerted by these novel triazine molecules qualified them as potential anti-Alzheimer drug candidates in AD therapy.

KEYWORDS:

ADME analysis; Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Molecular docking; Triazine; Triazolopyrimidine quinoline

PMID:
28478343
DOI:
10.1016/j.ejmech.2017.04.064
[Indexed for MEDLINE]

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