title: Rational design and synthesis of dihydropyrimidine based dual binding site acetylcholinesterase inhibitors.
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 IC50values 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.
authors.affiliation: Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
authors.forename: Sufyan
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
authors.forename: Fatima
authors.initials: F
authors.lastname: Iftikhar
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, 18000 Dir (L), Pakistan.
authors.forename: Farhat
authors.initials: F
authors.lastname: Ullah
authors.affiliation: Department of Pharmacy, University of Malakand, Chakdara, 18000 Dir (L), Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Sadiq
authors.affiliation: 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.
authors.forename: Umer
authors.initials: U
authors.lastname: Rashid
mesh_terms: D065567:Absorption, Physiological; D000110:Acetylcholinesterase / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D011743:Pyrimidines; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Blood brain barrier; Butyrylcholinesterase; Dihydropyrimidines; Dual binding site