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Divergent structure-activity relationships of structurally similar acetylcholinesterase inhibitors.

Andersson CD, Forsgren N, Akfur C, Allgardsson A, Berg L, Engdahl C, Qian W, Ekström F, Linusson A
J Med Chem 56 7615-24 (2013)
Related entries: 4b7z, 4b80, 4b81, 4b82, 4b83, 4b84, 4b85

Cited: 19 times
EuropePMC logo PMID: 23984975

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.

Reviews citing this publication (1)

  1. Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease. Ismaili L, Refouvelet B, Benchekroun M, Brogi S, Brindisi M, Gemma S, Campiani G, Filipic S, Agbaba D, Esteban G, Unzeta M, Nikolic K, Butini S, Marco-Contelles J. Prog Neurobiol 151 4-34 (2017)

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  1. Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors. Liu HR, Liu XJ, Fan HQ, Tang JJ, Gao XH, Liu WK. Bioorg Med Chem 22 6124-6133 (2014)
  2. Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates. Katz FS, Pecic S, Tran TH, Trakht I, Schneider L, Zhu Z, Ton-That L, Luzac M, Zlatanic V, Damera S, Macdonald J, Landry DW, Tong L, Stojanovic MN. Chembiochem 16 2205-2215 (2015)
  3. Amine substitution of quinazolinones leads to selective nanomolar AChE inhibitors with 'inverted' binding mode. Darras FH, Wehle S, Huang G, Sotriffer CA, Decker M. Bioorg Med Chem 22 4867-4881 (2014)
  4. The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes. Berg L, Mishra BK, Andersson CD, Ekström F, Linusson A. Chemistry 22 2672-2681 (2016)
  5. N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes. Knutsson S, Kindahl T, Engdahl C, Nikjoo D, Forsgren N, Kitur S, Ekström F, Kamau L, Linusson A. Eur J Med Chem 134 415-427 (2017)
  6. Synthesis and Evaluation of the 4-Substituted 2-Hydroxy-5-Iodochalcones and Their 7-Substituted 6-Iodoflavonol Derivatives for Inhibitory Effect on Cholinesterases and β-Secretase. Mphahlele MJ, Agbo EN, Gildenhuys S. Int J Mol Sci 19 E4112 (2018)
  7. Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase. Andersson CD, Hillgren JM, Lindgren C, Qian W, Akfur C, Berg L, Ekström F, Linusson A. J Comput Aided Mol Des 29 199-215 (2015)
  8. 1-(3-Tert-Butylphenyl)-2,2,2-Trifluoroethanone as a Potent Transition-State Analogue Slow-Binding Inhibitor of Human Acetylcholinesterase: Kinetic, MD and QM/MM Studies. Zueva IV, Lushchekina SV, Pottie IR, Darvesh S, Masson P. Biomolecules 10 E1608 (2020)
  9. An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet. Allgardsson A, David Andersson C, Akfur C, Worek F, Linusson A, Ekström F. Molecules 22 E1433 (2017)
  10. Synthesis, Biological Evaluation and Molecular Modelling of 2'-Hydroxychalcones as Acetylcholinesterase Inhibitors. Sukumaran SD, Chee CF, Viswanathan G, Buckle MJ, Othman R, Abd Rahman N, Chung LY. Molecules 21 E955 (2016)
  11. Acetylcholinesterase of the sand fly, Phlebotomus papatasi (Scopoli): construction, expression and biochemical properties of the G119S orthologous mutant. Temeyer KB, Tong F, Totrov MM, Tuckow AP, Chen QH, Carlier PR, Pérez de León AA, Bloomquist JR. Parasit Vectors 7 577 (2014)
  12. Discovery of Novel Tryptanthrin Derivatives with Benzenesulfonamide Substituents as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease. Wang G, Du J, Ma J, Liu P, Xing S, Xia J, Dong S, Li Z. Pharmaceuticals (Basel) 16 1468 (2023)
  13. Physical Mechanisms Governing Substituent Effects on Arene-Arene Interactions in a Protein Milieu. Andersson CD, Mishra BK, Forsgren N, Ekström F, Linusson A. J Phys Chem B 124 6529-6539 (2020)
  14. Protective effects of a piperazine derivative [N-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-phenyl} carbamic acid ethyl ester] against aluminium-induced neurotoxicity: insights from in silico and in vivo studies. Meena P, Manral A, Saini V, Tiwari M. Neurotox Res 27 314-327 (2015)
  15. Evaluating Fmoc-amino acids as selective inhibitors of butyrylcholinesterase. Gonzalez J, Ramirez J, Schwans JP. Amino Acids 48 2755-2763 (2016)
  16. Numerical calculation of protein-ligand binding rates through solution of the Smoluchowski equation using smoothed particle hydrodynamics. Pan W, Daily M, Baker NA. BMC Biophys 8 7 (2015)
  17. Structure-Activity Relationships Reveal Beneficial Selectivity Profiles of Inhibitors Targeting Acetylcholinesterase of Disease-Transmitting Mosquitoes. Vidal-Albalat A, Kindahl T, Rajeshwari R, Lindgren C, Forsgren N, Kitur S, Tengo LS, Ekström F, Kamau L, Linusson A. J Med Chem 66 6333-6353 (2023)
  18. Toxicological Evaluation and In Silico Identification of Acetylcholinesterase Inhibitors in a Commercial Polyherbal Formulation (KWAPF01). Aladodo AR, Ibrahim IO, Sabiu S. Evid Based Complement Alternat Med 2022 4388941 (2022)


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