title: Adamantane-substituted guanylhydrazones: novel inhibitors of butyrylcholinesterase.
abstract: A series of novel adamantane-substituted guanylhydrazones was synthesized and used in a study of inhibitory potential toward butyrylcholinesterase. The experimental results were further supported by using docking studies to examine the behavior of the inhibitors within the active site regions of the enzyme. The enzyme-inhibitor dissociation constants K(i) were determined from Hunter-Downs diagrams using Ellman's method for cholinesterase activity determination. Compounds 2-(N-guanidino)iminoadamantane hydrochloride (1) and 2,4-bis(N,N'-guanidino)iminoadamantane dihydrochloride (2) were found to be the best BChE inhibitors and their affinities for the enzyme active site were about five times higher compared to the enzyme peripheral site. The strongest interaction observed in complexes obtained by docking studies was the H-bond between the guanidine and the carboxylate of Glu199 and the second guanidine group in bisguanidine compounds was stabilized with additional H-bonds.
authors.affiliation: Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, P.O. Box 180, 10002 Zagreb, Croatia.
authors.forename: Marina
authors.initials: M
authors.lastname: Sekutor
authors.forename: Kata
authors.initials: K
authors.lastname: Mlinarić-Majerski
authors.forename: Tomica
authors.initials: T
authors.lastname: Hrenar
authors.forename: Srđanka
authors.initials: S
authors.lastname: Tomić
authors.forename: Ines
authors.initials: I
authors.lastname: Primožič
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D006835:Hydrazones; D002091:Butyrylcholinesterase; D000218:Adamantane