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

Sufyan Ahmad; Fatima Iftikhar; Farhat Ullah; Abdul Sadiq; Umer Rashid

doi:10.1016/j.bioorg.2016.10.002

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

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

Authors

Sufyan Ahmad¹, Fatima Iftikhar¹, Farhat Ullah², Abdul Sadiq², Umer Rashid³

Affiliations

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.

PMID: 27750058
DOI: 10.1016/j.bioorg.2016.10.002

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.

MeSH terms

Absorption, Physiological
Acetylcholinesterase / metabolism*
Binding Sites / drug effects
Blood-Brain Barrier / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Intestinal Mucosa / metabolism
Intestines / drug effects
Molecular Docking Simulation
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Pyrimidines
Acetylcholinesterase