Adamantane-substituted guanylhydrazones: Novel inhibitors of butyrylcholinesterase

• Published in: Bioorganic chemistry 2012-04, Vol.41-42, p.28-34
• Main Authors: Šekutor, Marina, Mlinarić-Majerski, Kata, Hrenar, Tomica, Tomić, Srđanka, Primožič, Ines
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Adamantane - chemical synthesis; Adamantane - chemistry; Adamantane-substituted guanylhydrazones; Binding Sites; Butyrylcholinesterase; Butyrylcholinesterase - chemistry; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Humans; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrogen Bonding; Inhibitors; Kinetic study; Kinetics; Models, Molecular; Molecular docking; Molecular Structure; Protein Binding; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2012.01.004

A series of novel adamantane-substituted guanylhydrazones was synthesized and used in a study of inhibitory potential toward butyrylcholinesterase. The inhibition constants were determined and docking studies performed to examine the behavior of the inhibitors within the active site regions of the enzyme. The strongest interactions observed in complexes obtained by docking studies were numerous H-bonds of the guanidine group. [Display omitted] ► Several novel adamantane-substituted guanylhydrazones were synthesized. ► Inhibitory potentials (Ki) toward butyrylcholinesterase were determined. ► Docking studies gave insight on how the inhibitors interact with the enzyme. ► The most important interactions were numerous hydrogen bonds of guanidine groups. 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 Ki 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.