Inhibitory effects of novel benzamide derivatives towards acetylcholinesterase enzyme

Year 2021, , 429 - 434, 31.05.2021

Cem Yamalı , Halise İnci Gül , Serkan Levent , Yeliz Demir

https://doi.org/10.18596/jotcsa.842465

Abstract

Alzheimer's disease is one of the diseases which is identified by progressive memory loss and cognitive deficits leading to a decline in the lifespan of the patients. The drugs used in the clinic show palliative properties and they are unable to modify disease progression. In this study, N-(4-(N-(diaminomethylene)sulfamoyl)phenyl)-2-(substituted-benzamido)benzamide derivatives were synthesized and evaluated towards acetylcholinesterase (AChE, E.C.3.1.1.7) enzyme which is the most studied enzyme regarding Alzheimer's disease. The inhibition constants (Ki) of the compounds synthesized towards the AChE enzyme were in the range of 15.51 ± 1.88 - 41.24 ± 10.13 nM. The most effective compound with the lowest Ki = 15.51 ± 1.88 nM, 2-benzamido-N-(4-(N-(diaminomethylene)sulfamoyl)phenyl)benzamide 6, can be reported as a lead compound of this study. Bioactivity results obtained by this study may provide useful information on the development of novel and potent inhibitors targeting Alzheimer's disease.

Keywords

Acetylcholinesterase, sulfaguanidine, Alzheimer's disease

Thanks

We would like thank to Prof. Dr. Ilhami Gulcin for his valuable scientific supports.

References

• 1. Wajid S, Khatoon A, Khan MA, Zafar H, Kanwal S et al. Microwave-assisted organic synthesis, structure-activity relationship, kinetics and molecular docking studies of non-cytotoxic benzamide derivatives as selective butyrylcholinesterase inhibitors. Bioorganic and Medicinal Chemistry. 2019;27(18): 4030-40. doi: 10.1016/j.bmc.2019.07.015
• 2. Kratky M, Stepankova S, Vorcakova K, Svarcova M, Vinsova J. Novel cholinesterase inhibitors based on O-aromatic N,N-disubstituted carbamates and thiocarbamates. Molecules. 2016;21(2): 191-01. doi: 10.3390/molecules21020191
• 3. Oliveira C, Bagetta D, Cagide F, Teixeira J, Amorim R, Silva T, et al. Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents. European Journal of Medicinal Chemistry. 2019;174:116-29. doi: 10.1016/j.ejmech.2019.04.026
• 4. Peng DY, Sun Q, Zhu XL, Lin HY, Chen Q, Yu NX, et al. Design, synthesis, and bioevaluation of benzamides: novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, A? aggregation, and ?-secretase. Bioorganic and Medicinal Chemistry. 2012;20(22):6739-50. doi: 10.1016/j.bmc.2012.09.016
• 5. https://www.nia.nih.gov/health/how-alzheimers-disease-treated, December 2020.
• 6. Darras FH, Kling B, Sawatzky E, Heilmann J, Decker M. Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase. Bioorganic and Medicinal Chemistry. 2014;22(17):5020-34. doi: 10.1016/j.bmc.2014.06.010
• 7. Yiannopoulou KG, Papageorgiou SG. Current and future treatments for Alzheimer's disease. Therapeutic Advances in Neurological Disorders. 2013;6(1):19-33. doi: 10.1177/1756285612461679
• 8. Sekutor M, Mlinaric-Majerski K, Hrenar T, Tomic S, Primozic I. Adamantane-substituted guanylhydrazones: novel inhibitors of butyrylcholinesterase. Bioorganic Chemistry. 2012;41-42:28-34. doi: 10.1016/j.bioorg.2012.01.004
• 9. Gul HI, Yamali C, Bulbuller M, Kirmizibayrak PB, Gul M, Angeli A, et al. Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes. Bioorganic Chemistry. 2018;78:290-97. doi: 10.1016/j.bioorg.2018.03.027
• 10. Gul HI, Yamali C, Sakagami H, Angeli A, Leitans J, Kazaks A, et al. New anticancer drug candidates sulfonamides as selective hCA IX or hCA XII inhibitors. Bioorganic Chemistry. 2018;77:411-19. doi: 10.1016/j.bioorg.2018.01.021
• 11. Yamali C, Gul HI, Ece A, Taslimi P, Gulcin I. Synthesis, molecular modeling, and biological evaluation of 4-(5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl) benzenesulfonamides toward acetylcholinesterase, carbonic anhydrase I and II enzymes. Chemical Biology and Drug Design. 2018;91(4):854-66. doi: 10.1111/cbdd.13149
• 12. Yamali C, Gul HI, Kazaz C, Levent S, Gulcin I. Synthesis, structure elucidation, and in vitro pharmacological evaluation of novel polyfluoro substituted pyrazoline type sulfonamides as multi-target agents for inhibition of acetylcholinesterase and carbonic anhydrase I and II enzymes. Bioorganic Chemistry. 2020;96:103627. doi: 10.1016/j.bioorg.2020.103627
• 13. Zhu J, Yang HY, Chen Y, Lin HZ, Li Q, Mo J, et al. Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease. Journal of Enzym Inhibition and Medicinal Chemistry. 2018;33(1):496-06. doi: 10.1080/14756366.2018.1430691
• 14. Asundaria ST, Patel NS, Patel KC. Synthesis, characterization, and antimicrobial studies of novel 1,3,4-thiadiazolium-5-thiolates. Medicinal Chemistry Research. 2012;21:1199-06. doi: 10.1007/s00044-011-9632-2
• 15. Ellman GL, Courtney KD, Andres V, Jr., Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology. 1961;7:88-95. doi: 10.1016/0006-2952(61)90145-9
• 16. Yamali C, Gu HI, Demir Y, Kazaz C, Gulcin I. Synthesis and bioactivities of 1-(4-hydroxyphenyl)-2-((heteroaryl) thio) ethanones as carbonic anhydrase I, II and acetylcholinesterase inhibitors. Turkish Journal of Chemistry. 2020; 44(4), 1058-67. doi:10.3906/kim-2004-36
• 17. Yamali C, Gul HI, Cakir T, Demir Y, Gulcin I. Aminoalkylated Phenolic Chalcones: Investigation of Biological Effects on Acetylcholinesterase and carbonic anhydrase I and II as potential lead enzyme inhibitors. Letters in Drug Design and Discovery. 2002;17(10): 1283-92. doi: 10.2174/1570180817999200520123510
• 18. Selvam P, Vijayalakshimi P, Smee DF, Gowen BB, Julander JG, Day CW, et al. Novel 3-sulphonamido-quinazolin-4(3H)-one derivatives: microwave-assisted synthesis and evaluation of antiviral activities against respiratory and biodefense viruses. Antiviral Chemistry and Chemotherapy. 2007;18(5):301-05. doi: 10.1177/095632020701800506
• 19. Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. Applications of fluorine in medicinal chemistry. Journal of Medicinal Chemistry. 2015;58(21):8315-59. doi: 10.1021/acs.jmedchem.5b00258
• 20. Yamali C, Gul HI, Ozgun DO, Sakagami H, Umemura N, Kazaz C, et al. Synthesis and cytotoxic activities of difluoro-dimethoxy chalcones. Anticancer Agents in Medicinal Chemistry. 2017;17(10):1426-33. doi: 10.2174/1871520617666170327123909
• 21. Yamali C, Ozgun DO, Gul HI et al. Synthesis and structure elucidation of 1-(2,5/3,5-difluorophenyl)-3-(2,3/2,4/2,5/3,4-dimethoxyphenyl)-2-propen-1-ones as anticancer agents. Medicinal Chemistry Research 2017;26:2015-23. doi: 10.1007/s00044-017-1911-0