Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors

Forsgren, Nina (author): Swedish Defense Research Agency, CBRN Defense and Security, Umeå

Akfur, Christine (author): Swedish Defense Research Agency, CBRN Defense and Security, Umeå

Allgardsson, Anders (author): Swedish Defense Research Agency, CBRN Defense and Security, Umeå

Engdahl, Cecilia (author): Umeå universitet,Kemiska institutionen,Swedish Defense Research Agency, CBRN Defense and Security, Umeå

Qian, Weixing (author): Umeå universitet,Kemiska institutionen,Laboratories for Chemical Biology Umeå (LCBU), Umeå University,

Ekström, Fredrik (author): Swedish Defense Research Agency, CBRN Defense and Security, Umeå

(creator_code:org_t)

2013-09-19
2013
English.
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:19, s. 7615-7624

Related links:: https://urn.kb.se/re...; show more...; https://doi.org/10.1...; show less...

Abstract Subject headings

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.

By the author/editor: Andersson, C. Da ...; Forsgren, Nina; Akfur, Christine; Allgardsson, And ...; Berg, Lotta; Engdahl, Cecilia; show more...; Qian, Weixing; Ekström, Fredrik; Linusson, Anna; show less...

About the subject

ENGINEERING AND TECHNOLOGY: ENGINEERING AND ...; and Chemical Enginee ...; and Pharmaceutical C ...

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