Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Medicinal Chemistry
  4. Fast Track Articles
  5. Fast Track Article
image of Synthesis of 2,4-Bis(trifluoromethyl)benzaldehyde Hybrid Thiosemicarbazones as Prolyl Oligopeptidase Inhibitors for Neurodegenerative Disorders and their In-silico Analysis

Abstract

Introduction

Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia.

Method

The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde-based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC 10.14 - 41.73 M).

Result

Compound 3a emerged as the most active compound (IC 10.14 ± 0.72 M) of the series. The kinetic study of the most active 3a ( =13.66 0.0012 M) indicated competitive inhibition of the aforementioned enzyme.

Conclusion

Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673325023240909101327
2024-10-14
2024-11-26

  • From This Site

    /content/journals/cmc/10.2174/0109298673325023240909101327
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Krátký M. Svrčková K. Vu Q.A. Štěpánková Š. Vinšová J. Hydrazones of 4-(trifluoromethyl) benzohydrazide as new inhibitors of acetyl-and butyrylcholinesterase. Molecules 2021 26 4 989 10.3390/molecules26040989 33668452
    [Google Scholar]
  2. Nair A.S. Singh A.K. Kumar A. Kumar S. Sukumaran S. Koyiparambath V.P. Pappachen L.K. Rangarajan T.M. Kim H. Mathew B. FDA-approved trifluoromethyl group-containing Drugs: A review of 20 years. Processes 2022 10 10 2054 10.3390/pr10102054
    [Google Scholar]
  3. O’Hagan D. Fluorine in health care: Organofluorine containing blockbuster drugs. J. Fluor. Chem. 2010 131 11 1071 1081 10.1016/j.jfluchem.2010.03.003
    [Google Scholar]
  4. Swallow S. Fluorine in medicinal chemistry. Prog. Med. Chem. 2015 54 65 133 10.1016/bs.pmch.2014.11.001 25727703
    [Google Scholar]
  5. da Silva Santos J. de Melos J.L.R. Lima G.S. Lyra J.C. Guedes G.P. Rodrigues-Santos C.E. Echevarria A. Synthesis, anti-Trypanosoma cruzi activity and quantitative structure relationships of some fluorinated thiosemicarbazones. J. Fluor. Chem. 2017 195 31 36 10.1016/j.jfluchem.2017.01.013
    [Google Scholar]
  6. Wang J. Sánchez-Roselló M. Aceña J.L. del Pozo C. Sorochinsky A.E. Fustero S. Soloshonok V.A. Liu H. Fluorine in pharmaceutical industry: Fluorine-containing drugs introduced to the market in the last decade (2001-2011). Chem. Rev. 2014 114 4 2432 2506 10.1021/cr4002879 24299176
    [Google Scholar]
  7. Hagmann W.K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 2008 51 15 4359 4369 10.1021/jm800219f 18570365
    [Google Scholar]
  8. Abula A. Xu Z. Zhu Z. Peng C. Chen Z. Zhu W. Aisa H.A. Substitution effect of the trifluoromethyl group on the bioactivity in medicinal chemistry: Statistical analysis and energy calculations. J. Chem. Inf. Model. 2020 60 12 6242 6250 10.1021/acs.jcim.0c00898 33258377
    [Google Scholar]
  9. Podar K. Shah J. Chari A. Richardson P.G. Jagannath S. Selinexor for the treatment of multiple myeloma. Expert Opin. Pharmacother. 2020 21 4 399 408 10.1080/14656566.2019.1707184 31957504
    [Google Scholar]
  10. Mucker E.M. Goff A.J. Shamblin J.D. Grosenbach D.W. Damon I.K. Mehal J.M. Holman R.C. Carroll D. Gallardo N. Olson V.A. Clemmons C.J. Hudson P. Hruby D.E. Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox). Antimicrob. Agents Chemother. 2013 57 12 6246 6253 10.1128/AAC.00977‑13 24100494
    [Google Scholar]
  11. Scott L.J. Ubrogepant: First approval. Drugs 2020 80 3 323 328 10.1007/s40265‑020‑01264‑5 32020557
    [Google Scholar]
  12. Islam M. Khan A. Shehzad M.T. Khiat M. Halim S.A. Hameed A. Shah S.R. Basri R. Anwar M.U. Hussain J. Csuk R. Al-Harrasi A. Shafiq Z. Therapeutic potential of N-substituted thiosemicarbazones as new urease inhibitors: Biochemical and in silico approach. Bioorg. Chem. 2021 109 104691 10.1016/j.bioorg.2021.104691 33601138
    [Google Scholar]
  13. Rasool A. Batool Z. Khan M. Halim S.A. Shafiq Z. Temirak A. Salem M.A. Ali T.E. Khan A. Al-Harrasi A. Bis-pharmacophore of cinnamaldehyde-clubbed thiosemicarbazones as potent carbonic anhydrase-II inhibitors. Sci. Rep. 2022 12 1 16095 10.1038/s41598‑022‑19975‑y 36167735
    [Google Scholar]
  14. Basri R. Ahmed N. Khalid M. Khan M.U. Abdullah M. Syed A. Elgorban A.M. Al-Rejaie S.S. Braga A.A.C. Shafiq Z. Quinoline based thiosemicarbazones as colorimetric chemosensors for fluoride and cyanide ions and DFT studies. Sci. Rep. 2022 12 1 4927 10.1038/s41598‑022‑08860‑3 35322108
    [Google Scholar]
  15. Pasha A.R. Khalid M. Shafiq Z. Khan M.U. Naseer M.M. Tahir M.N. Hussain R. Braga A.A.C. Jawaria R. A comprehensive study of structural, non-covalent interactions and electronic insights into N-aryl substituted thiosemicarbazones via SC-XRD and first-principles DFT approach. J. Mol. Struct. 2021 1230 129852 10.1016/j.molstruc.2020.129852
    [Google Scholar]
  16. Zhang X. Huang J. Zhang Y. Qi F. Wang S. Song J. Synthesis, crystal structure and non-covalent interactions analysis of novel N-substituted thiosemicarbazone. Chem. Res. Chin. Univ. 2019 35 3 471 477 10.1007/s40242‑019‑8354‑8
    [Google Scholar]
  17. Ruiz R. García B. Garcia-Tojal J. Busto N. Ibeas S. Leal J.M. Martins C. Gaspar J. Borrás J. Gil-García R. González-Álvarez M. Biological assays and noncovalent interactions of pyridine-2-carbaldehyde thiosemicarbazonecopper(II) drugs with [poly(dA–dT)]2, [poly(dG–dC)]2, and calf thymus DNA. J. Biol. Inorg. Chem. 2010 15 4 515 532 10.1007/s00775‑009‑0620‑7 20087612
    [Google Scholar]
  18. Basri R. Ullah S. Khan A. Mali S.N. Abchir O. Chtita S. El-Gokha A. Taslimi P. Binsaleh A.Y. El-kott A.F. Al-Harrasi A. Shafiq Z. Synthesis, biological evaluation and molecular modelling of 3-Formyl-6-isopropylchromone derived thiosemicarbazones as α-glucosidase inhibitors. Bioorg. Chem. 2023 139 106739 10.1016/j.bioorg.2023.106739 37478545
    [Google Scholar]
  19. Pasha A.R. Ullah S. Khan A. al-Rashida M. Islam T. Hussain J. Batool Z. Kashtoh H. Abdellattif M.H. Al-Harrasi A. Shafiq Z. Synthesis, in vitro α-glucosidase inhibitory potential and in silico study of 2‑chloro pyridine incorporated thiosemicarbazones. J. Mol. Struct. 2024 1317 139089 10.1016/j.molstruc.2024.139089
    [Google Scholar]
  20. PapeVeronika F. Anticancer thiosemicarbazones: Chemical properties, interaction with iron metabolism, and resistance development. Antioxid. Redox Signal. 2019 30 8 10.1089/ars.2017.7487
    [Google Scholar]
  21. Khan S.A. Kumar P. Joshi R. Iqbal P.F. Saleem K. Synthesis and in vitro antibacterial activity of new steroidal thiosemicarbazone derivatives. Eur. J. Med. Chem. 2008 43 9 2029 2034 10.1016/j.ejmech.2007.12.004 18450330
    [Google Scholar]
  22. Khanye S.D. Smith G.S. Lategan C. Smith P.J. Gut J. Rosenthal P.J. Chibale K. Synthesis and in vitro evaluation of gold(I) thiosemicarbazone complexes for antimalarial activity. J. Inorg. Biochem. 2010 104 10 1079 1083 10.1016/j.jinorgbio.2010.06.005 20621360
    [Google Scholar]
  23. Paiva R.O. Kneipp L.F. Goular C.M. Albuquerque M.A. Echevarria A. Antifungal activities of thiosemicarbazones and semicarbazones against mycotoxigenic fungi. Cienc. Agrotec. 2014 38 6 531 537 10.1590/S1413‑70542014000600001
    [Google Scholar]
  24. Soraires Santacruz M.C. Fabiani M. Castro E.F. Cavallaro L.V. Finkielsztein L.M. Synthesis, antiviral evaluation and molecular docking studies of N4-aryl substituted/unsubstituted thiosemicarbazones derived from 1-indanones as potent anti-bovine viral diarrhea virus agents. Bioorg. Med. Chem. 2017 25 15 4055 4063 10.1016/j.bmc.2017.05.056 28600079
    [Google Scholar]
  25. Ishaq M. Taslimi P. Shafiq Z. Khan S. Ekhteiari Salmas R. Zangeneh M.M. Saeed A. Zangeneh A. Sadeghian N. Asari A. Mohamad H. Synthesis, bioactivity and binding energy calculations of novel 3-ethoxysalicylaldehyde based thiosemicarbazone derivatives. Bioorg. Chem. 2020 100 103924 10.1016/j.bioorg.2020.103924 32442818
    [Google Scholar]
  26. Yang G. Xu C. Zhao M. Wang C. Fan S. Xie P. Li X. Microwave assisted one-pot synthesis of novel trifluoromethyl coumarin thiosemicarbazones and their antifungal activities. Curr. Microw. Chem. 2015 3 1 60 67 10.2174/2213335602666150702161715
    [Google Scholar]
  27. Mavroidi B. Kaminari A. Matiadis D. Hadjipavlou-Litina D. Pelecanou M. Tzinia A. Sagnou M. The prophylactic and multimodal activity of two isatin thiosemicarbazones against Alzheimer’s disease in vitro. Brain Sci. 2022 12 6 806 10.3390/brainsci12060806 35741690
    [Google Scholar]
  28. Osmaniye D. Kurban B. Sağlık B.N. Levent S. Özkay Y. Kaplancıklı Z.A. Novel thiosemicarbazone derivatives: In vitro and in silico evaluation as potential MAO-B inhibitors. Molecules 2021 26 21 6640 10.3390/molecules26216640 34771054
    [Google Scholar]
  29. Pasha A.R. Khan A. Ullah S. Halim S.A. Alharthy R.D. Anwar M.U. Hussain J. Naseer M.M. Kashtoh H. Al-Harrasi A. Shafiq Z. Boshta N.M. Indole-based thiosemicarbazones for neurodegenerative diseases as prolyl oligopeptidase inhibitors. J. Mol. Struct. 2024 1312 138666 10.1016/j.molstruc.2024.138666
    [Google Scholar]
  30. Shan L. Mathews I.I. Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. Proc. Natl. Acad. Sci. USA 2005 102 10 3599 3604 10.1073/pnas.0408286102 15738423
    [Google Scholar]
  31. Bruce L.A. Cyr N.E. Qiao J.W. DeFries C.C. Tetel M.J. Wolfson A.J. Neuropeptidase activity is down-regulated by estradiol in steroid-sensitive regions of the hypothalamus in female mice. Neuropeptides 2012 46 4 167 172 10.1016/j.npep.2012.04.002 22672888
    [Google Scholar]
  32. Wang M.X. Zhong C. Cai Q-F. Liu G-M. Zhang L. Hara K. Su W-J. Cao M-J. Study on a prolyl endopeptidase from the skeletal muscle of common carp (Cyprinus carpio). Process Biochem. 2012 47 12 2211 2218 10.1016/j.procbio.2012.08.016
    [Google Scholar]
  33. Shirenova S.D. Khlebnikova N.N. Krupina N.A. Long-term social isolation reduces expression of the BDNF precursor and prolyl endopeptidase in the rat brain. Biochemistry 2021 86 6 704 715 10.1134/S0006297921060080 34225593
    [Google Scholar]
  34. Khan A. Waqas M. Khan M. Halim S.A. Rehman N.U. Al-Harrasi A. Identification of novel prolyl oligopeptidase inhibitors from resin of Boswellia papyrifera (Del.) Hochst. and their mechanism: Virtual and biochemical studies. Int. J. Biol. Macromol. 2022 213 751 767 10.1016/j.ijbiomac.2022.06.001 35679958
    [Google Scholar]
  35. Brandt I. Gérard M. Sergeant K. Devreese B. Baekelandt V. Augustyns K. Scharpé S. Engelborghs Y. Lambeir A.M. Prolyl oligopeptidase stimulates the aggregation of α-synuclein. Peptides 2008 29 9 1472 1478 10.1016/j.peptides.2008.05.005 18571285
    [Google Scholar]
  36. Stepniak D. Spaenij-Dekking L. Mitea C. Moester M. de Ru A. Baak-Pablo R. van Veelen P. Edens L. Koning F. Highly efficient gluten degradation with a newly identified prolyl endoprotease: Implications for celiac disease. Am. J. Physiol. Gastrointest. Liver Physiol. 2006 291 4 G621 G629 10.1152/ajpgi.00034.2006 16690904
    [Google Scholar]
  37. Männistö P.T. García-Horsman J.A. Mechanism of action of prolyl oligopeptidase (PREP) in degenerative brain diseases: Has peptidase activity only a modulatory role on the interactions of PREP with proteins? Front. Aging Neurosci. 2017 9 27 10.3389/fnagi.2017.00027 28261087
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673325023240909101327
Loading
Synthesis of 2,4-Bis(trifluoromethyl)benzaldehyde Hybrid Thiosemicarbazones as Prolyl Oligopeptidase Inhibitors for Neurodegenerative Disorders and their In-silico Analysis
Bentham Science Publishers ; https://doi.org/10.2174/0109298673325023240909101327
/content/journals/cmc/10.2174/0109298673325023240909101327
/content/journals/cmc/10.2174/0109298673325023240909101327
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: 2,4-Bis(trifluoromethyl)benzaldehyde ; molecular docking ; kinetics ; thiosemicarbazone ; prolyl endo-peptidase inhibitors

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test