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Bioorg Chem. 2016 Dec;69:91-101. doi: 10.1016/j.bioorg.2016.10.002. Epub 2016 Oct 11.

Rational design and synthesis of dihydropyrimidine based dual binding site acetylcholinesterase inhibitors.

Author information

1
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
2
Department of Pharmacy, University of Malakand, Chakdara, 18000 Dir (L), Pakistan.
3
Department of Chemistry, Hazara University, Mansehra 21120, Pakistan; Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: umerrashid@ciit.net.pk.

Abstract

Based on the pharmacological importance of dihydropyrimidine (DHPM) scaffold, substituted DHPMs linked with acetamide linker to substituted aromatic anilines were synthesized and evaluated for their potency as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The good AChE inhibitory activity of 4-dihydropyrimidine-2-thione (4a-h) and 2-amino-1,4-dihyropyrimidines (5a-h) series was observed with compound 4a and 4d identified as the most potent compounds with IC50 values of 0.17±0.01 and 0.39±0.04μMrespectively. The inhibition of BChE was found in a broader range of concentrations (2.37-56.32μM). To explore the binding insights into the enzyme, molecular docking study was carried out using GOLD software. The binding mode analysis indicated that all of these inhibitors are well accommodated in the active site and interact with the key amino acid residues of Catalytic anionic site (CAS) and peripheral anionic site (PAS). Furthermore, in silico ADMET predictions suggest that these compounds are non-AMES toxic with good blood brain barrier (BBB) penetration, human intestinal absorption.

KEYWORDS:

Acetylcholinesterase; Blood brain barrier; Butyrylcholinesterase; Dihydropyrimidines; Dual binding site

PMID:
27750058
DOI:
10.1016/j.bioorg.2016.10.002
[Indexed for MEDLINE]

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