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Synthesis of hydrazine containing piperazine or benzimidazole derivatives and their potential as α-amylase inhibitors by molecular docking, inhibition kinetics and in vitro cytotoxicity activity studies

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Abstract

The α-amylase is the main product of pancreas and is necessarily involved in the hydrolysis of carbohydrates into glucose so that it has been known to be a pioneer target for type 2 Diabetes mellitus (DM). Type 2 DM has no certain cure and the global increase in the cases of DM requires effective and extensive number of drug candidates. Drug discovery studies using organic biochemistry approaches are of important to describe novel compounds. This study aimed to reveal inhibitory potential of 13 novel compounds containing piperazine or benzimidazole moieties on α-amylase. The novel compounds were synthesized, structurally corroborated by various spectral analysis (FTIR, UV-Vis, 1H NMR and 13C NMR) and screened for anti α-amylase activity. Among the synthesized derivatives, compound 14 was found to be the most potent inhibitor of α-amylase having IC50 64.8 ± 1.8 μM. Inhibition types and Ki values of the most effective molecules (14 and 10a with different moieties) were further investigated. Molecular docking studies were conducted to correlate the outcome of in vitro biochemical kinetic assays and therefore rationalize the binding interactions. In vitro cytotoxicity studies on pancreatic cancer (AR42J) cells were then performed for compound14, and the compound was found to be more effective compared to the positive control, acarbose. Prediction of in silico ADME properties of all tested molecules were determined.

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Data availability

The datasets generated during/or analyzed during the current study are available from the corresponding author on reasonable request. The datasets supporting the results of this paper are included within the paper and its additional files.

References

  1. Borah PK, Sarkar A, Duary RK. Water-soluble vitamins for controlling starch digestion: Conformational scrambling and inhibition mechanism of human pancreatic α-amylase by ascorbic acid and folic acid. Food Chem. 2019;288:395–404.

    Article  CAS  PubMed  Google Scholar 

  2. Ganesan MS, Kanmani Raja K, Narasimhan K, Murugesan S, Karan Kumar B. Design, synthesis, α-amylase inhibition and in silico docking study of novel quinoline bearing proline derivatives. J Mol Struct. 2020;1208:127873.

    Article  CAS  Google Scholar 

  3. Cardullo N, Muccilli V, Pulvirenti L, Cornu A, Pouységu L, Deffieux D, et al. C-glucosidic ellagitannins and galloylated glucoses as potential functional food ingredients with anti-diabetic properties: a study of α-glucosidase and α-amylase inhibition. Food Chem. 2020;313:126099.

    Article  PubMed  CAS  Google Scholar 

  4. Zheng Y, Tian J, Yang W, Chen S, Liu D, Fang H, et al. Inhibition mechanism of ferulic acid against α-amylase and α-glucosidase. Food Chem. 2020;317:126346.

    Article  CAS  PubMed  Google Scholar 

  5. Hemlata B, Pornima G, Tukaram K, Pankaj B. In vitro anti-amylase activity of some Indian dietary spices. J Appl Biol Biotechnol. 2019;7:70–4.

    Article  CAS  Google Scholar 

  6. Woodford N. Biological counterstrike: antibiotic resistance mechanisms of gram-positive cocci. Clin Microbiol Infect. 2005;23:2–21.

    Article  Google Scholar 

  7. Maruyama T, Kano Y, Yamamoto Y, Kurazono M, Iwamatsu K, Atsumi K, et al. Synthesis and SAR study of novel 7-(pyridinium-3-yl)-carbonyl imidazo[5,1-b]thiazol-2-yl carbapenems. Bioorg Med Chem. 2007;15:392–402.

    Article  CAS  PubMed  Google Scholar 

  8. Demirbas A, Sahin D, Demirbas N, Karaoglu SA. Synthesis of some new 1,3,4-thiadiazol-2-ylmethyl-1,2,4-triazole derivatives and investigation of their antimicrobial activities. Eur J Med Chem. 2009;44:2896–903.

    Article  CAS  PubMed  Google Scholar 

  9. Barbuceanu SF, Saramet G, Almajan LG, Draghici C, Barbuceanu F, Bancescu G. New heterocyclic compounds from 1,2,4-triazole and 1,3,4-thiadiazole class bearing diphenylsulfone moieties. Synthesis, characterization and antimicrobial activity evaluation. Eur J Med Chem. 2012;49:417–23.

    Article  CAS  PubMed  Google Scholar 

  10. Deng X, Qiu Q, Yang B, Wang X, Huang W, Qian H. Design, synthesis and biological evaluation of novel peptides with anti-cancer and drug resistance-reversing activities. Eur J Med Chem. 2015;89:540–8. 2015

    Article  CAS  PubMed  Google Scholar 

  11. Basoglu S, Ulker S, Alpay-Karaoglu S, Demirbas N. Microwave-assisted synthesis of some hybrid molecules containing penicillanic acid or cephalosporanic acid moieties and investigation of their biological activities. Med Chem Res. 2014;23:3128–43.

    Article  CAS  PubMed  Google Scholar 

  12. Sharma S, Wakode F, Fayaz S, Khasimbi F, Pottoo H, Kaur A. An overview of piperazine scaffold as promising nucleus for different therapeutic targets. Curr Pharm Des. 2020;26:1–13.

    Article  CAS  Google Scholar 

  13. Adegboye AA, Khan KM, Salar U, Aboaba SA, Kanwal, Chigurupati S, et al. 2-Aryl benzimidazoles: Synthesis, in vitro α-amylase inhibitory activity, and molecular docking study. Eur J Med Chem. 2018;150:248–60.

    Article  CAS  PubMed  Google Scholar 

  14. Kazimierczuk ZJ, Upcroft A, Upcroft P, Gorska A, Starosciak B, Laudy A. Synthesis, antiprotozoal and antibacterial activity of nitro- and halogeno-substituted benzimidazole derivatives. Acta Biochim Pol. 2002;49:185–95.

    Article  CAS  PubMed  Google Scholar 

  15. Ansari KF, Lal C. Synthesis, physicochemical properties and anti-microbial activity of some new benzimidazole derivatives. Eur J Med Chem. 2009;44:4028–33.

    Article  CAS  PubMed  Google Scholar 

  16. Macalino SJY, Gosu V, Hong S, Choi S. Role of computer-aided drug design in modern drug discovery. Arch Pharm Res. 2015;38:1686–701.

    Article  CAS  PubMed  Google Scholar 

  17. Trott O, Olson AJ. Auto Dock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31:455–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des. 2011;7:146–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pagadala NS, Syed K, Tuszynski J. Software for molecular docking: a review. Biophys Rev. 2017;9:91–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules. 2015;20:13384–421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rajanarendar E, Thirupathaiah K, Ramakrishna S, Nagaraju D. A facile and convenient synthesis of novel imidazo[1,2-b] isoxazoles and their Mannich bases as potential biodynamic agents. Chin Chem Lett. 2015;26:1511–3.

    Article  CAS  Google Scholar 

  22. Mentese MY, Bayrak H, Uygun Y, Mermer A, Ulker S, Karaoğlu SA, et al. Microwave assisted synthesis of some hybrid molecules derived from norfloxacin and investigation of their biological activities. Eur J Med Chem. 2013;67:230–42.

    Article  CAS  PubMed  Google Scholar 

  23. Balabani A, Hadjipavlou-Litina DJ, Litinas KE, Mainou M, Tsironi CC, Vronteli A. Synthesis and biological evaluation of (2,5-dihydro-1H-pyrrol-1-yl)-2H-chromen-2-ones as free radical scavengers. Eur J Med Chem. 2011;46:5894–901.

    Article  CAS  PubMed  Google Scholar 

  24. Bayrak H, Demirbas A, Demirbas N, Karaoglu SA. Synthesis of some new 1,2,4-triazoles starting from isonicotinic acid hydrazide and evaluation of their antimicrobial activities. Eur J Med Chem. 2009;44:4362–6.

    Article  CAS  PubMed  Google Scholar 

  25. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997;23:3–25.

    Article  CAS  Google Scholar 

  26. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45:2615–23.

    Article  CAS  PubMed  Google Scholar 

  27. Matsuura Y. A possible mechanism of catalysis involving three essential residues in the enzymes of alpha-amylase family. Biol-Bratisl. 2002;57:21–8.

    CAS  Google Scholar 

  28. Gilles C, Astier JP, Marchis-Mouren G, Cambillau C, Payan F. Crystal structure of pig pancreatic α‐amylase isoenzyme II, in complex with the carbohydrate inhibitor acarbose. Eur J Biochem. 1996;238:561–9.

    Article  CAS  PubMed  Google Scholar 

  29. Wang J, Zhao J, Yan Y, Liu D, Wang C, Wang H. Inhibition of glycosidase by ursolic acid: In vitro, in vivo and in silico study. J Sci Food Agric. 2020;100:986–94.

    Article  CAS  PubMed  Google Scholar 

  30. Mohammadi-Khanaposhtani M, Rezaei S, Khalifeh R, Imanparast S, Faramarzi MA, Bahadorikhalili S, et al. Design, synthesis, docking study, alpha-glucosidase inhibition, and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes. Bioorg Chem. 2018;80:288–95.

    Article  CAS  PubMed  Google Scholar 

  31. Yadav V, Talwar P. Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: an underestimated truth. Biomed. 2019;111:934.

    CAS  Google Scholar 

  32. Idowu T, Schweizer F. Ubiquitous nature of fluoroquinolones: the oscillation between antibacterial and anticancer activities. Antibiotics. 2017;6:26.

    Article  PubMed Central  CAS  Google Scholar 

  33. Nishi K, Kato M, Sakurai S, Matsumoto A, Iwase Y, Yumita N. Enoxacin with UVA irradiation induces apoptosis in the AsPC1 human pancreatic cancer cell line through ROS generation. Anticancer Res. 2017;37:6211.

    CAS  PubMed  Google Scholar 

  34. Beberok A, Wrześniok D, Rok J, Rzepka Z, Respondek M, Buszman E. Ciprofloxacin triggers the apoptosis of human triple-negative breast cancer MDAMB- 231 cells via the p53/Bax/Bcl-2 signaling pathway. Int J Oncol. 2018;52:1727–37.

    CAS  PubMed  Google Scholar 

  35. Beberok A, Wrześniok D, Minecka A, Rok J, Delijewski M, Rzepka Z, et al. Ciprofloxacin-mediated induction of S-phase cell cycle arrest and apoptosis in COLO829 melanoma cells. Pharmacol Rep. 2018;70:6.

    Article  CAS  PubMed  Google Scholar 

  36. Yu M, Li R, Zhang J. Repositioning of antibiotic levofloxacin as a mitochondrial biogenesis inhibitor to target breast cancer. Biochem Biophys Res Commun. 2016;471:639–45.

    Article  CAS  PubMed  Google Scholar 

  37. Song M, Wu H, Wu S, Ge T, Wang G, Zhou Y, et al. Antibiotic drug levofloxacin inhibits proliferation and induces apoptosis of lung cancer cells through inducing mitochondrial dysfunction and oxidative damage. Biomed Pharm Ther. 2016;84:1137.

    Article  CAS  Google Scholar 

  38. Jemel-Oualha I, Elloumi-Mseddi J, Beji A, Hakim B, Aifa S. Controversial effect on Erk activation of some cytotoxic drugs in human LOVO colon cancer cells. J Recept Transduct Res. 2016;36:21.

    CAS  Google Scholar 

  39. Sousa E, Graça I, Baptista T, Vieira FQ, Palmeira C, Henrique R, et al. Enoxacin inhibits growth of prostate cancer cells and effectively restores microRNA processing. Epigenetics. 2013;8:548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Azema J, Guidetti B, Korolyov A, Kiss R, Roques C, Constant P, et al. Synthesis of lipophilic dimeric C-7/C-7-linked ciprofloxacin and C-6/C-6-linked levofloxacin derivatives. Versatile in vitro biological evaluations of monomeric and dimeric fluoroquinolone derivatives as potential antitumor, antibacterial or antimycobacterial agents. Eur J Med Chem. 2011;46:6025.

    Article  CAS  PubMed  Google Scholar 

  41. Hu G, Wang G, Duan N, Wen X, Cao T, Xie S, et al. Design, synthesis and antitumor activities of fluoroquinolone C-3 heterocycles (IV): s-triazole Schiff–Mannich bases derived from ofloxacin. Acta Pharm Sin B. 2012;2:312.

    Article  CAS  Google Scholar 

  42. Dixit S, Mishra N, Sharma M, Singh S, Agarwal A, Awassthi SK, et al. Synthesis and in vitro antiplasmodial activities of fluoroquinolone analogs. Eur J Med Chem. 2012;51:52.

    Article  CAS  PubMed  Google Scholar 

  43. Gürbay A, Osman M, Favier A, Hincal F. Ciprofloxacin-Induced Cytotoxicity and Apoptosis in HeLa Cells. Toxicol Mech Methods. 2005;15:339.

    Article  PubMed  CAS  Google Scholar 

  44. Basoglu-Ozdemir S. Synthesis of novel fluoroquinolone-triazole hybrid compounds as antimicrobial agents. J Turkish Chem Soc Sect Chem. 2016;3:515–34.

    Article  Google Scholar 

  45. Menteşe M, Demirbaş N, Mermer A, Demirci S, Demirbaş A, Ayaz FA. Novel azole-functionalited flouroquinolone hybrids: design, conventional and microwave ırradiated synthesis, evaluation as antibacterial and antioxidant agents. Lett Drug Des Discov. 2017;15:46–64.

    Article  CAS  Google Scholar 

  46. Taha M, Baharudin MS, Ismail NH, Imran S, Khan MN, Rahim F, et al. Synthesis, α-amylase inhibitory potential and molecular docking study of indole derivatives. Bioorg Chem. 2018;80:36–42.

    Article  CAS  PubMed  Google Scholar 

  47. Kolcuoglu Y, Colak A, Faiz O, Belduz AO. Cloning, expression and characterization of highly thermo- and pH-stable maltogenic amylase from a thermophilic bacterium Geobacillus caldoxylosilyticus TK4. Proc Biochem. 2010;45:821–8.

    Article  CAS  Google Scholar 

  48. Lineweaver H, Burk D. The determination of enzyme dissociation constant. J Am Chem Soc. 1934;56:658–61.

    Article  CAS  Google Scholar 

  49. Lv X, Bai R, Yan J-K, Huang H-L, Huo X-K, Tian X-G, et al. Investigation of the inhibitory effect of protostanes on human carboxylesterase 2 and their interaction: inhibition kinetics and molecular stimulations. Int J Biol Macromol. 2021;167:1262–72.

    Article  CAS  PubMed  Google Scholar 

  50. Sun C-P, Yan J-K, Yi J, Zhang X-Y, Yu Z-L, Huo X-K, et al. The study of inhibitory effect of natural flavonoids toward β-glucuronidase and interaction off lavonoids with β-glucuronidase. Int J Biol Macromol. 2020;143:349–58.

    Article  CAS  PubMed  Google Scholar 

  51. Zhao W-Y, Yan J-J, Zhang M, Wang C, Feng L, Lv X, et al. Natural soluble epoxide hydrolase inhibitors from Inula britanica and their potential interactions with soluble epoxide hydrolase: Insight from inhibition kinetics and molecular Dynamics. Chem Biol Interact. 2021;345:109571.

    Article  CAS  PubMed  Google Scholar 

  52. Molinspiration Cheminformatics, http://www.molinspiration.com/cgibin/properties.

  53. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7.1:1–13.

    Google Scholar 

  54. Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, Beck G, et al. Rate-limited steps of human oral absorption and QSAR studies. Pharm Res. 2002;19:1446–57.

    Article  CAS  PubMed  Google Scholar 

  55. Spartan’16 Wavefunction, Inc. Irvine, CA.

  56. Stewart JJP. Application of the pm6 method to modeling proteins. J Mol Model. 2009;15:765–805.

    Article  CAS  PubMed  Google Scholar 

  57. Zhao Y, Truhlar DG. Density functionals with broad applicability in chemistry. Acc Chem Res. 2008;41:157–67.

    Article  CAS  PubMed  Google Scholar 

  58. Zhao Y, Truhlar DG. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Acc. 2008;120:215–41.

    Article  CAS  Google Scholar 

  59. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;16:2785–91.

    Article  CAS  Google Scholar 

  60. Grosdidier A, Zoete V, Michielin O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res. 2011;39:W270–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Grosdidier A, Zoete V, Michielin O. Fast docking using the CHARMM force field with EADock DSS. J Comput Chem. 2011;32:2149–59.

    Article  CAS  PubMed  Google Scholar 

  62. BIOVIA, D. S. Discovery Studio Modeling Environment, Release 4.5, San Diego: Dassault Systèmes, 2015.

  63. Demir S, Aliyazicioglu Y, Turan I, Misir S, Mentese A, Ozer-Yaman S, et al. Antiproliferative and proapoptotic activity of Turkish propolis on human lung cancer cell line. Nutr Cancer. 2016;68:165–72.

    Article  PubMed  Google Scholar 

  64. Demir S, Turan I, Aliyazicioglu Y, Kilinc K, Ozer Yaman S, Ayazoglu Demir E, et al. Morus rubra extract induces cell cycle arrest and apoptosis in human colon cancer cells through endoplasmic reticulum stress and telomerase. Nutr Cancer. 2017;69:74.

    Article  PubMed  Google Scholar 

  65. Eichler HG, Korn A, Gasic S, Pirson W, Businger J. The effect of a new specific alpha-amylase inhibitor on post-prandial glucose and insulin excursions in normal subjects and type-2 (non-insulin-dependent) diabetic-patients. Diabetologia. 1984;26:278–81.

    Article  CAS  PubMed  Google Scholar 

  66. Creutzfeldt W. The [pre-] history of the incretin concept. Regulatory Pept. 2005;128:87–91.

    Article  CAS  Google Scholar 

  67. Ayazoglu-Demir E, Demir S, Aliyazıcıoglu Y. In vitro cytotoxic effect of ethanol and dimethyl sulfoxide on various human cell lines. KSU J Agric Nat Scope Focus. 2020;23:1119–24.

    Google Scholar 

  68. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.

    Article  CAS  PubMed  Google Scholar 

  69. Wang HM, Chen CY, Chen CY, Ho ML, Chou YT, Chang HC, et al. (-)-N-Formylanonaine from Michelia alba as a human tyrosinase inhibitor and antioxidant. Bioorg Med Chem. 2010;18:5241–7.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Karadeniz Technical University, 61080, Trabzon, Turkey

    Ummuhan Cakmak, Fulya Oz-Tuncay, Serap Basoglu-Ozdemir, Ahmet Colak & Nuri Yildirim

  2. Department of Chemistry and Chemistry Processing Technologies, Macka Vocational High School, Karadeniz Technical University, 61750, Trabzon, Turkey

    Elif Ayazoglu-Demir

  3. Department of Chemistry, Faculty of Arts and Sciences, Marmara University, 34722, Istanbul, Turkey

    İlke Demir & Safiye Sag Erdem

  4. Department of Molecular Biology and Genetics, Faculty of Science, Karadeniz Technical University, 61080, Trabzon, Turkey

    Selcen Celik-Uzuner

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  1. Ummuhan Cakmak
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  2. Fulya Oz-Tuncay
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  3. Serap Basoglu-Ozdemir
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  4. Elif Ayazoglu-Demir
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Contributions

UC: Methodology, Formal analysis, Investigation, Writing—Original draft, Writing—Review & Editing, Visualization, Data curation. FOT: Methodology, Formal analysis, Investigation, Writing—Original draft. SBO: Methodology, Formal analysis, Investigation, Writing—Original draft, Visualization, Data curation. EA-D: Formal analysis, Investigation, Writing—Original draft. ID: Methodology, Software, Formal analysis, Investigation, Writing—Original Draft, Visualization. AC: Conceptualization, Resources, Supervision, Writing—Original draft, Writing—Review & Editing Project administration, Funding acquisition. SC-U: Methodology, Resources. SSE: Methodology, Software, Resources. NY: Formal analysis, Resources.

Funding

The authors are grateful to the Research Fund of the TUBITAK (The Scientific and Technological Research Council of Turkey) or this support with Project No 117Z199.

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Correspondence to Ahmet Colak.

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Cakmak, U., Oz-Tuncay, F., Basoglu-Ozdemir, S. et al. Synthesis of hydrazine containing piperazine or benzimidazole derivatives and their potential as α-amylase inhibitors by molecular docking, inhibition kinetics and in vitro cytotoxicity activity studies. Med Chem Res 30, 1886–1904 (2021). https://doi.org/10.1007/s00044-021-02785-8

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