title: Divergent structure-activity relationships of structurally similar acetylcholinesterase inhibitors.
abstract: The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure-activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.
authors.affiliation: Department of Chemistry, Umeå University , SE-901 87 Umeå, Sweden.
authors.forename: C David
authors.initials: CD
authors.lastname: Andersson
authors.forename: Nina
authors.initials: N
authors.lastname: Forsgren
authors.forename: Christine
authors.initials: C
authors.lastname: Akfur
authors.forename: Anders
authors.initials: A
authors.lastname: Allgardsson
authors.forename: Lotta
authors.initials: L
authors.lastname: Berg
authors.forename: Cecilia
authors.initials: C
authors.lastname: Engdahl
authors.forename: Weixing
authors.initials: W
authors.lastname: Qian
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ekström
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D018360:Crystallography, X-Ray; D057075:Enzyme Assays; D004793:Enzyme Reactivators / Q000737:chemistry; D006868:Hydrolysis; D051379:Mice; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D001555:Benzene Derivatives; D001713:Biphenyl Compounds; D002800:Cholinesterase Inhibitors; D004793:Enzyme Reactivators; D009281:Naphthalenes; D013449:Sulfonamides; D000110:Acetylcholinesterase