Advertisement

Molecular docking and investigation of 4-(benzylideneamino)- and 4-(benzylamino)-benzenesulfonamide derivatives as potent AChE inhibitors

  • Mesut IşıkEmail author
  • Yeliz Demir
  • Mustafa Durgun
  • Cüneyt Türkeş
  • Adem Necip
  • Şükrü Beydemir
Original Paper
  • 35 Downloads

Abstract

The discovery of acetylcholinesterase inhibitors is important for the treatment of Alzheimer’s disease (AD), known as the most common type of dementia. Due to the side effects of commonly used acetylcholinesterase inhibitors, studies for the detection of new inhibitors are increasing day by day. In this study, we investigated the effects of some sulfonamide derivatives (S1–S4 and S1i–S4i) on AChE enzymes. The best pose of the active compounds to understand the mechanism of possible inhibition in interaction of enzyme-sulfonamide derivative were performed docking studies after in vitro experimental results. ADME-related physicochemical and pharmacokinetic properties of the synthesized 4-aminobenzenesulfonamide derivatives were the compatibility with Lipinski’s rule of five. We found that the synthesized derivatives of sulfonamides show potential inhibitor properties for AChE with Ki constants in the range of 2.54 ± 0.22–299.60 ± 8.73 µM. The derivatives of sulfonamides exhibited different inhibition type. We determined that the derivatives (S1, S1i, S3, and S3i) showed a competitive inhibition effect, whereas others (S2, S2i, S4, and S4i) showed mixed-type inhibition. As a result, the sulfonamide derivatives can be used as an alternative acetylcholinesterase inhibitor due to this effect. Inhibitors with fewer side effects, are thought to be important in the treatment of AD.

Keywords

Sulfonamide derivatives Alzheimer AChE inhibitor Molecular docking Pharmacokinetic properties 

Notes

Acknowledgements

The authors are grateful for the financial support provided by the Research Foundation of Harran University (Project no. 16180).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11696_2019_988_MOESM1_ESM.docx (93 kb)
Supplementary material 1 (DOCX 93 kb)

References

  1. Andreani A et al (2001) Synthesis and screening for antiacetylcholinesterase activity of (1-benzyl-4-oxopiperidin-3-ylidene) methylindoles and-pyrroles related to donepezil. J Med Chem 44:4011–4014.  https://doi.org/10.1021/jm0109356 CrossRefPubMedGoogle Scholar
  2. Bag S et al (2015) Sulfonamides as multifunctional agents for Alzheimer’s disease. Bioorg Med Chem Lett 25:626–630.  https://doi.org/10.1016/j.bmcl.2014.12.006 CrossRefPubMedGoogle Scholar
  3. Bartolini M, Bertucci C, Cavrini V, Andrisano V (2003) β-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol 65:407–416.  https://doi.org/10.1016/S0006-2952(02)01514-9 CrossRefPubMedGoogle Scholar
  4. Belluti F et al (2009) Design, synthesis, and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors. Eur J Med Chem 44:1341–1348.  https://doi.org/10.1016/j.ejmech.2008.02.035 CrossRefPubMedGoogle Scholar
  5. Benzi G, Moretti A (1998) Is there a rationale for the use of acetylcholinesterase inhibitors in the therapy of Alzheimer’s disease? Eur J Pharmacol 346:1–13.  https://doi.org/10.1016/S0014-2999(98)00093-4 CrossRefPubMedGoogle Scholar
  6. Beydemir Ş, Türkeş C, Yalçın A (2019) Gadolinium-based contrast agents: in vitro paraoxonase 1 inhibition, in silico studies. Drug Chem Toxicol.  https://doi.org/10.1080/01480545.2019.1620266 CrossRefPubMedGoogle Scholar
  7. Caglayan C, Demir Y, Kucukler S, Taslimi P, Kandemir FM, Gulçin İ (2019) The effects of hesperidin on sodium arsenite-induced different organ toxicity in rats on metabolic enzymes as antidiabetic and anticholinergics potentials: a biochemical approach. J Food Biochem 43:e12720.  https://doi.org/10.1111/jfbc.12720 CrossRefPubMedGoogle Scholar
  8. Çağlayan C, Taslimi P, Demir Y, Küçükler S, Kandemir FM, Gulçin İ (2019) The effects of zingerone against vancomycin-induced lung, liver, kidney and testis toxicity in rats: the behavior of some metabolic enzymes. J Biochem Mol Toxicol.  https://doi.org/10.1002/jbt.22381 CrossRefPubMedGoogle Scholar
  9. Choudhary MI (2001) Bioactive natural products as a potential source of new pharmacophores. A theory of memory. Pure Appl Chem 73:555–560.  https://doi.org/10.1351/pac200173030555 CrossRefGoogle Scholar
  10. Davis T (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2:1403CrossRefGoogle Scholar
  11. de Oliveira AS et al (2016) New sulfonamides derived from carvacrol: compounds with high antibacterial activity against resistant staphylococcus aureus strains. J Biosci Med 4:105.  https://doi.org/10.4236/jbm.2016.47011 CrossRefGoogle Scholar
  12. Demir Y, Işık M, Gülçin İ, Beydemir Ş (2017) Phenolic compounds inhibit the aldose reductase enzyme from the sheep kidney. J Biochem Mol Toxicol 31:e21936.  https://doi.org/10.1002/jbt.21935 CrossRefGoogle Scholar
  13. Durgun M, Turkmen H, Ceruso M, Supuran CT (2016) Synthesis of 4-sulfamoylphenyl-benzylamine derivatives with inhibitory activity against human carbonic anhydrase isoforms I, II, IX and XII. Bioorg Med Chem 24:982–988.  https://doi.org/10.1016/j.bmc.2016.01.020 CrossRefPubMedGoogle Scholar
  14. Ellman GL, Courtney KD, Andres V Jr, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95.  https://doi.org/10.1016/0006-2952(61)90145-9 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Erdemir F et al (2019) Novel 2-aminopyridine liganded Pd (II) N-heterocyclic carbene complexes: synthesis, characterization, crystal structure and bioactivity properties. Bioorg Chem 91:103134.  https://doi.org/10.1016/j.bioorg.2019.103134 CrossRefPubMedGoogle Scholar
  16. Eroglu E, Türkmen H (2007) A DFT-based quantum theoretic QSAR study of aromatic and heterocyclic sulfonamides as carbonic anhydrase inhibitors against isozyme, CA-II. J Mol Graph Model 26:701–708.  https://doi.org/10.1016/j.jmgm.2007.03.015 CrossRefPubMedGoogle Scholar
  17. Friesner RA et al (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749.  https://doi.org/10.1021/jm0306430 CrossRefPubMedGoogle Scholar
  18. García-Ayllón M-S, Small DH, Avila J, Sáez-Valero J (2011) Revisiting the role of acetylcholinesterase in Alzheimer’s disease: cross-talk with P-tau and β-amyloid. Front Mol Neurosci 4:22.  https://doi.org/10.3389/fnmol.2011.00022 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Genç Y, Özkanca R, Bekdemir Y (2008) Antimicrobial activity of some sulfonamide derivatives on clinical isolates of Staphylococus aureus. Ann Clin Microbiol Antimicrob 7:17.  https://doi.org/10.1186/1476-0711-7-17 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Geula C, Mesulam M (1989) Special properties of cholinesterases in the cerebral cortex of Alzheimer’s disease. Brain Res 498:185–189.  https://doi.org/10.1016/0006-8993(89)90419-8 CrossRefPubMedGoogle Scholar
  21. Göçer H, Akincioğlu A, Göksu S, Gülçin İ, Supuran CT (2015) Carbonic anhydrase and acetylcholinesterase inhibitory effects of carbamates and sulfamoylcarbamates. J Enzyme Inhib Med Chem 30:316–320.  https://doi.org/10.3109/14756366.2014.928704 CrossRefPubMedGoogle Scholar
  22. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47:1750–1759.  https://doi.org/10.1021/jm030644s CrossRefPubMedGoogle Scholar
  23. Harder E et al (2015) OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. J Chem Theory Comput 12:281–296.  https://doi.org/10.1021/acs.jctc.5b00864 CrossRefPubMedGoogle Scholar
  24. Ignasik M, Bajda M, Guzior N, Prinz M, Holzgrabe U, Malawska B (2012) Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1, 3-dione derivatives as dual-binding site acetylcholinesterase inhibitors. Arch Pharm 345:509–516.  https://doi.org/10.1002/ardp.201100423 CrossRefGoogle Scholar
  25. Imbimbo BP (2001) Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer’s disease. CNS Drugs 15:375–390.  https://doi.org/10.2165/00023210-200115050-00004 CrossRefPubMedGoogle Scholar
  26. Işık M (2019) The binding mechanisms and inhibitory effect of intravenous anesthetics on AChE in vitro and in vivo: kinetic analysis and molecular docking. Neurochem Res.  https://doi.org/10.1007/s11064-019-02852-y CrossRefPubMedGoogle Scholar
  27. Işık M, Demir Y, Kırıcı M, Demir R, Şimşek F, Beydemir Ş (2015) Changes in the anti-oxidant system in adult epilepsy patients receiving anti-epileptic drugs. Arch Physiol Biochem 121:97–102.  https://doi.org/10.3109/13813455.2015.1026912 CrossRefPubMedGoogle Scholar
  28. Işık M, Beydemir Ş, Yılmaz A, Naldan ME, Aslan HE, Gülçin İ (2017) Oxidative stress and mRNA expression of acetylcholinesterase in the leukocytes of ischemic patients. Biomed Pharmacother 87:561–567.  https://doi.org/10.1016/j.biopha.2017.01.003 CrossRefPubMedGoogle Scholar
  29. Köksal Z, Alım Z, Bayrak S, Gülçin İ, Özdemir H (2019) Investigation of the effects of some sulfonamides on acetylcholinesterase and carbonic anhydrase enzymes. J Biochem Mol Toxicol 33:e22300.  https://doi.org/10.1002/jbt.22300 CrossRefPubMedGoogle Scholar
  30. Kołaczek A, Fusiarz I, Ławecka J, Branowska D (2014) Biological activity and synthesis of sulfonamide derivatives: a brief review. Chemik 68:620–628Google Scholar
  31. Kucukoglu K, Gul HI, Taslimi P, Gulcin I, Supuran CT (2019) Investigation of inhibitory properties of some hydrazone compounds on hCA I, hCA II and AChE enzymes. Bioorg Chem 86:316–321.  https://doi.org/10.1016/j.bioorg.2019.02.008 CrossRefPubMedGoogle Scholar
  32. Lineweaver H, Burk D (1934) The determination of enzyme dissociation constants. J Am Chem Soc 56:658–666.  https://doi.org/10.1021/ja01318a036 CrossRefGoogle Scholar
  33. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25.  https://doi.org/10.1016/S0169-409X(96)00423-1 CrossRefGoogle Scholar
  34. Liston DR et al (2004) Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer’s disease. Eur J Pharmacol 486:9–17.  https://doi.org/10.1016/j.ejphar.2003.11.080 CrossRefPubMedGoogle Scholar
  35. Martinez A, Fernandez E, Castro A, Conde S, Rodriguez-Franco I, Baños J-E, Badia A (2000) N-Benzylpiperidine derivatives of 1, 2, 4-thiadiazolidinone as new acetylcholinesterase inhibitors. Eur J Med Chem 35:913–922.  https://doi.org/10.1016/S0223-5234(00)01166-1 CrossRefPubMedGoogle Scholar
  36. Mukherjee PK, Kumar V, Mal M, Houghton PJ (2007) Acetylcholinesterase inhibitors from plants. Phytomedicine 14:289–300.  https://doi.org/10.1016/j.phymed.2007.02.002 CrossRefPubMedGoogle Scholar
  37. Mutahir S et al (2016) Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: synthesis, biological evaluation and molecular modeling studies. Bioorg Chem 64:13–20.  https://doi.org/10.1016/j.bioorg.2015.11.002 CrossRefPubMedGoogle Scholar
  38. Oh M, Houghton P, Whang W, Cho J (2004) Screening of Korean herbal medicines used to improve cognitive function for anti-cholinesterase activity. Phytomedicine 11:544–548.  https://doi.org/10.1016/j.phymed.2004.03.001 CrossRefPubMedGoogle Scholar
  39. Parihar MS, Hemnani T (2004) Alzheimer’s disease pathogenesis and therapeutic interventions. J Clin Neurosci 11:456–467.  https://doi.org/10.1016/j.jocn.2003.12.007 CrossRefPubMedGoogle Scholar
  40. Rusted JM, Warburton DM (1992) Facilitation of memory by post-trial administration of nicotine: evidence for an attentional explanation. Psychopharmacology 108:452–455.  https://doi.org/10.1007/BF02247420 CrossRefPubMedGoogle Scholar
  41. Sakkiah S, Lee KW (2012) Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors. Acta Pharmacol Sin 33:964.  https://doi.org/10.1038/aps.2012.21 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Santos MA, Marques SM, Tuccinardi T, Carelli P, Panelli L, Rossello A (2006) Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors. Bioorg Med Chem 14:7539–7550.  https://doi.org/10.1016/j.bmc.2006.07.011 CrossRefPubMedGoogle Scholar
  43. Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221–234.  https://doi.org/10.1007/s10822-013-9644-8 CrossRefPubMedGoogle Scholar
  44. Schätz CR, Geula C, Mesulam M (1990) Competitive substrate inhibition in the histochemistry of cholinesterase activity in Alzheimer’s disease. Neurosci Lett 117:56–61.  https://doi.org/10.1016/0304-3940(90)90119-T CrossRefPubMedGoogle Scholar
  45. Scozzafava A, Mastrolorenzo A, Supuran CT (2002) Sulfonamides and sulfonylated derivatives as anticancer agents. Curr Cancer Drug Targets 2:55–75.  https://doi.org/10.2174/1568009023334060 CrossRefPubMedGoogle Scholar
  46. Singh M, Kaur M, Kukreja H, Chugh R, Silakari O, Singh D (2013) Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection. Eur J Med Chem 70:165–188.  https://doi.org/10.1016/j.ejmech.2013.09.050 CrossRefPubMedGoogle Scholar
  47. Turkan F, Cetin A, Taslimi P, Gulçin İ (2018) Some pyrazoles derivatives: potent carbonic anhydrase, α-glycosidase, and cholinesterase enzymes inhibitors. Arch Pharm 351:1800200.  https://doi.org/10.1002/ardp.201800200 CrossRefGoogle Scholar
  48. Türkan F, Huyut Z, Demir Y, Ertaş F, Beydemir Ş (2019) The effects of some cephalosporins on acetylcholinesterase and glutathione S-transferase: an in vivo and in vitro study. Arch Physiol Biochem 125:235–243.  https://doi.org/10.1080/13813455.2018.1452037 CrossRefPubMedGoogle Scholar
  49. Türkeş C (2019a) A potential risk factor for paraoxonase 1: in silico and in-vitro analysis of the biological activity of proton-pump inhibitors. J Pharm Pharmacol 71:1553–1564.  https://doi.org/10.1111/jphp.13141 CrossRefPubMedGoogle Scholar
  50. Türkeş C (2019b) Investigation of potential paraoxonase-I inhibitors by kinetic and molecular docking studies: chemotherapeutic drugs. Protein Pept Lett 26:392–402.  https://doi.org/10.2174/0929866526666190226162225 CrossRefPubMedGoogle Scholar
  51. Türkeş C (2019c) Inhibition effects of phenolic compounds on human serum paraoxonase-1 enzyme. J Inst Sci Technol 9:1013–1022.  https://doi.org/10.21597/jist.491054 CrossRefGoogle Scholar
  52. Türkeş C, Beydemir Ş (2019) Inhibition of human serum paraoxonase-I with antimycotic drugs: in vitro and in silico studies. Appl Biochem Biotechnol.  https://doi.org/10.1007/s12010-019-03073-3 CrossRefPubMedGoogle Scholar
  53. Türkeş C, Söyüt H, Beydemir Ş (2014) Effect of calcium channel blockers on paraoxonase-1 (PON1) activity and oxidative stress. Pharmacol Rep 66:74–80.  https://doi.org/10.1016/j.pharep.2013.08.007 CrossRefPubMedGoogle Scholar
  54. Türkeş C, Söyüt H, Beydemir Ş (2015) Human serum paraoxonase-1 (hPON1): in vitro inhibition effects of moxifloxacin hydrochloride, levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium. J Enzyme Inhib Med Chem 30:622–628.  https://doi.org/10.3109/14756366.2014.959511 CrossRefPubMedGoogle Scholar
  55. Türkeş C, Söyüt H, Beydemir Ş (2016) In vitro inhibitory effects of palonosetron hydrochloride, bevacizumab and cyclophosphamide on purified paraoxonase-I (hPON1) from human serum. Environ Toxicol Pharmacol 42:252–257.  https://doi.org/10.1016/j.etap.2015.11.024 CrossRefPubMedGoogle Scholar
  56. Türkeş C, Arslan M, Demir Y, Çoçaj L, Nixha AR, Beydemir Ş (2019a) Synthesis, biological evaluation and in silico studies of novel N-substituted phthalazine sulfonamide compounds as potent carbonic anhydrase and acetylcholinesterase inhibitors. Bioorg Chem 89:103004.  https://doi.org/10.1016/j.bioorg.2019.103004 CrossRefPubMedGoogle Scholar
  57. Türkeş C, Beydemir Ş, Küfrevioğlu Öİ (2019b) In vitro and in silico studies on the toxic effects of antibacterial drugs as human serum paraoxonase 1 inhibitor. ChemistrySelect 4:9731–9736.  https://doi.org/10.1002/slct.201902424 CrossRefGoogle Scholar
  58. Türkeş C, Demir Y, Beydemir Ş (2019c) Anti-diabetic properties of calcium channel blockers: inhibition effects on aldose reductase enzyme activity. Appl Biochem Biotechnol 189:318–329.  https://doi.org/10.1007/s12010-019-03009-x CrossRefPubMedGoogle Scholar
  59. von Bernhardi R, Alarcón R, Mezzano D, Fuentes P, Inestrosa NC (2005) Blood cells cholinesterase activity in early stage Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord 19:204–212.  https://doi.org/10.1159/000083500 CrossRefGoogle Scholar
  60. Wager TT, Chandrasekaran RY, Hou X, Troutman MD, Verhoest PR, Villalobos A, Will Y (2010) Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes. ACS Chem Neurosci 1:420–434.  https://doi.org/10.1021/cn100007x CrossRefPubMedPubMedCentralGoogle Scholar
  61. Weinstock M (1999) Selectivity of cholinesterase inhibition. CNS Drugs 12:307–323.  https://doi.org/10.2165/00023210-199912040-00005 CrossRefGoogle Scholar
  62. Yamali C, Gul HI, Ece A, Taslimi P, Gulcin I (2018) 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. Chem Biol Drug Des 91:854–866.  https://doi.org/10.1111/cbdd.13149 CrossRefPubMedGoogle Scholar
  63. Yiğit B, Yiğit M, Taslimi P, Gök Y, Gülçin İ (2018) Schiff bases and their amines: synthesis and discovery of carbonic anhydrase and acetylcholinesterase enzymes inhibitors. Arch Pharm 351:1800146.  https://doi.org/10.1002/ardp.201800146 CrossRefGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2019

Authors and Affiliations

  1. 1.Department of Pharmacy Services, Vocational School of Health ServicesHarran UniversityŞanlıurfaTurkey
  2. 2.Department of Pharmacy Services, Nihat Delibalta Göle Vocational High SchoolArdahan UniversityArdahanTurkey
  3. 3.Department of Chemistry, Faculty of Arts and SciencesHarran UniversityŞanlıurfaTurkey
  4. 4.Department of Biochemistry, Faculty of PharmacyErzincan Binali Yıldırım UniversityErzincanTurkey
  5. 5.Department of Biochemistry, Faculty of PharmacyAnadolu UniversityEskisehirTurkey

Personalised recommendations