title: Potential of aryl-urea-benzofuranylthiazoles hybrids as multitasking agents in Alzheimer's disease.
abstract: New benzofuranylthiazole derivatives containing the aryl-urea moiety were synthesized and evaluated in vitro as dual acetylcholinesterase (AChE)-butyrylcholinesterase (BuChE) inhibitors. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were assayed. The result showed that all the synthesized compounds exhibited inhibitory activity on both AChE and BuChE with 1-(4-(5-bromobenzofuran-2-yl)thiazol-2-yl)-3-(2-fluorophenyl)urea (e25, IC50 value of 3.85 μM) and 1-(4-iodophenyl)-3-(4-(5-nitrobenzofuran-2-yl)thiazol-2-yl)urea (e38, IC50 value of 2.03 μM) as the strongest inhibitors against AChE and BuChE, respectively. Compound e38 was 8.5-fold more potent than galanthamine. The selectivity index of e25 and e38 was 2.40 and 0.37 against AChE and BuChE, respectively. Compound e2, e4 and e11 (IC50 = 0.2, 0.5 and 1.13 μM, respectively) showed a better ABTS cation radical scavenging ability than the standard quercetin (IC50 = 1.18 μM). Best poses of compounds e38 on BuChE and e25 on AChE indicate that the thiazole ring and the amidic moiety are important sites of interaction with both ChEs. In addition, the benzofuran ring and phenyl ring are anchored to the side chains of both enzymes by π-π(pi-pi) interactions.
authors.affiliation: Bezmialem Vakif University, Faculty of Pharmacy, Department of Analytical and Medicinal Chemistry, 34093, Istanbul, Turkey.
authors.forename: Belma Zengin
authors.initials: BZ
authors.lastname: Kurt
authors.affiliation: Bezmialem Vakif University, Faculty of Pharmacy, Department of Analytical and Medicinal Chemistry, 34093, Istanbul, Turkey.
authors.forename: Isil
authors.initials: I
authors.lastname: Gazioglu
authors.affiliation: Department of Drug Sciences, University of Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, I-95125, Catania, Italy. Electronic address: basilelivia@gmail.com.
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.affiliation: Sakarya University, Pamukova Vocational High School, 54900, Sakarya, Turkey. Electronic address: fsonmez@sakarya.edu.tr.
authors.forename: Fatih
authors.initials: F
authors.lastname: Sonmez
authors.affiliation: Molecular Modelling Laboratory, Department of Food Science, University of Parma, Parco Area delle Scienze 17/A, Parma 43124, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ginex
authors.affiliation: Sakarya University, Faculty of Arts and Science, Department of Chemistry, 54055, Sakarya, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Kucukislamoglu
authors.affiliation: Department of Drug Sciences, University of Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, I-95125, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000652:urine*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use*; D014101:Torpedo; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D001572:Benzofurans; D002800:Cholinesterase Inhibitors; D013844:Thiazoles; D014508:Urea; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase; Antioxidant; Aryl–urea–benzofuranylthiazoles; Butyrylcholinesterase; Docking; Inhibitors