Divergent Structure鈥揂ctivity Relationships of Structurally Similar Acetylcholinesterase Inhibitors

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• 作者：C. David Andersson ; Nina Forsgren ; Christine Akfur ; Anders Allgardsson ; Lotta Berg ; Cecilia Engdahl ; Weixing Qian ; Fredrik Ekstr枚m ; Anna Linusson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 10, 2013
• 年：2013
• 卷：56
• 期：19
• 页码：7615-7624
• 全文大小：382K
• 年卷期：v.56,no.19(October 10, 2013)
• ISSN：1520-4804

文摘

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鈥?aromatic properties were varied to establish structure鈥揳ctivity 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.