Startseite Evaluation of 2-(1H-1,2,3-triazol-1-yl) acetic acid derivatives as potential human hypoxia-inducible factor (HIF) prolyl hydroxylase domain-2 (PHD2) inhibitors
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Evaluation of 2-(1H-1,2,3-triazol-1-yl) acetic acid derivatives as potential human hypoxia-inducible factor (HIF) prolyl hydroxylase domain-2 (PHD2) inhibitors

  • Abrar Mohammad Sayaf , June Sun Cheah , Abbas Khan , Christopher J. Schofield , Abdelali Agouni und Kar Kheng Yeoh EMAIL logo
Veröffentlicht/Copyright: 6. März 2025
Pure and Applied Chemistry
Aus der Zeitschrift Pure and Applied Chemistry Band 97 Heft 6

Abstract

The hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors can potentially treat ischemic and hypoxic-related diseases, as demonstrated by their use in anemia treatment. An AlphaScreen assay was utilized to assess the PHD2 inhibition of the 2-(1H-1,2,3-triazol-1-yl)acetic acid (TA) derivatives (1–14), which were synthesized using copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. Most of the TA derivatives did not inhibit PHD2 effectively, with compound 14 demonstrating weak inhibition at 100 µM (>50 %). Docking experiments revealed that 14 forms hydrogen bond interactions with Arg 383 and binds to the PHD2 active site iron in a bidentate manner. Molecular dynamic simulation analysis shows 14 resembles but differs from the positive control inhibitor bicyclic isoquinoline (BIQ). It displays stable dynamic characteristics, with some flexible areas stabilizing upon binding to PHD2. The total binding energies for BIQ-PHD2 and 14-PHD2 were determined to be −42.90 kcal/mol and −36.08 kcal/mol, respectively. These values suggest that 14 and BIQ have similar binding affinities. In conclusion, structural changes of 14 may result in the development of an effective PHD2 inhibitor. However, most TA derivatives showed strong binding in docking studies but did not demonstrate good inhibitory activity against PHD2.

Keywords: 1,2,3-triazole; HIF; hypoxia-inducible factor; ICYC 2024; PHD inhibitors; prolyl hydroxylase domain
Corresponding author: Kar Kheng Yeoh, School of Chemical Sciences, Universiti Sains Malaysia, Penang, 11800, Malaysia, e-mail:
Article note: A collection of invited papers based on presentations at the 9th International Conference for Young Chemists (ICYC 2024) held on 9–11 Oct 2024 in Penang, Malaysia.

Funding source: Fundamental Research Grant Scheme

Award Identifier / Grant number: FRGS/1/2021/STG04/USM/02/14

Acknowledgments

We thank the Ministry of Higher Education Malaysia (MOHE), Fundamental Research Grant Scheme (FRGS/1/2021/STG04/USM/02/14) for supporting this research.

  1. Research ethics: NA.

  2. Informed consent: NA.

  3. Author contributions: Abrar Mohammad Sayaf, Characterization, molecular docking , molecular dynamic simulation, analysis and original Draft writing. June Sun Cheah: Synthesis and characterization. Abbas Khan, Molecular dynamic simulation, analysis and writing. Christopher J. Schofield, Conceptualization, review and editing. Abdelali Agouni, Molecular dynamic simulation, analysis and writing. Kar Kheng Yeoh, Conceptualization, project administration, review, editing and hydroxylation assay. All authors agreed for manuscript submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: We use ChatGPT for grammatical checking.

  5. Conflict of interest: None.

  6. Research funding: FRGS/1/2021/STG04/USM/02/14.

  7. Data availability: Provided in supplementary data.

References

1. Palazon, A.; Goldrath, A.; Nizet, V.; Johnson, R. HIF Transcription Factors, Inflammation, and Immunity. Immunity 2014, 41 (4), 518–528; https://doi.org/10.1016/j.immuni.2014.09.008.Suche in Google Scholar PubMed PubMed Central

2. Taylor, C. T.; McElwain, J. C. Ancient Atmospheres and the Evolution of Oxygen Sensing via the Hypoxia-Inducible Factor in Metazoans. Physiology 2010, 25 (5), 272–279; https://doi.org/10.1152/physiol.00029.2010.Suche in Google Scholar PubMed

3. Hirota, K. HIF-α Prolyl Hydroxylase Inhibitors and their Implications for Biomedicine: A Comprehensive Review. Biomedicines 2021, 9 (5), 468; https://doi.org/10.3390/biomedicines9050468.Suche in Google Scholar PubMed PubMed Central

4. Strowitzki, M. J.; Cummins, E. P.; Taylor, C. T. Protein Hydroxylation by Hypoxia-Inducible Factor (Hif) Hydroxylases: Unique or Ubiquitous? Cells 2019, 8 (5), 384; https://doi.org/10.3390/cells8050384.Suche in Google Scholar PubMed PubMed Central

5. Poon, E.; Harris, A. L.; Ashcroft, M. Targeting the Hypoxia-Inducible Factor (Hif) Pathway in Cancer. Expet Rev. Mol. Med. 2009, 11, e26; https://doi.org/10.1017/s1462399409001173.Suche in Google Scholar PubMed

6. Bishop, T.; Ratcliffe, P. J. Hif Hydroxylase Pathways in Cardiovascular Physiology and Medicine. Circ. Res. 2015, 117 (1), 65–79; https://doi.org/10.1161/circresaha.117.305109.Suche in Google Scholar

7. Lisy, K.; Peet, D. Turn Me on: Regulating Hif Transcriptional Activity. Cell Death Differ. 2008, 15 (4), 642–649; https://doi.org/10.1038/sj.cdd.4402315.Suche in Google Scholar PubMed

8. Yeoh, K. K.; Chan, M. C.; Thalhammer, A.; Demetriades, M.; Chowdhury, R.; Tian, Y. M. Dual-Action Inhibitors of Hif Prolyl Hydroxylases that Induce Binding of a Second Iron Ion. Org. Biomol. Chem. 2013, 11 (5), 732–745; https://doi.org/10.1039/c2ob26648b.Suche in Google Scholar PubMed PubMed Central

9. Lee, J. W.; Ko, J.; Ju, C.; Eltzschig, H. K. Hypoxia Signaling in Human Diseases and Therapeutic Targets. Exp. Mol. Med. 2019, 51 (6), 1–13; https://doi.org/10.1038/s12276-019-0235-1.Suche in Google Scholar PubMed PubMed Central

10. Shyu, K. G.; Chang, H.; Sun, H. Y.; Wang, B. W.; Kuan, P. Carvedilol Modulates the Expression of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor in a Rat Model of Volume-Overload Heart Failure. J. Card. Fail. 2005, 11 (2), 152–159; https://doi.org/10.1016/j.cardfail.2004.06.433.Suche in Google Scholar PubMed

11. Lali, F. V.; Metcalfe, A. D. The Role of Angiogenesis in Wound Healing, Scarring and Tissue Regeneration. PMFA News 2014, 2 (1), 1–4.Suche in Google Scholar

12. Mace, K. A.; Yu, D. H.; Paydar, K. Z.; Boudreau, N.; Young, D. M. Sustained expression of HIF-1α in the diabetic environment promotes angiogenesis and cutaneous wound repair. Wound Repair Regen. 2007, 15 (5), 636–645; https://doi.org/10.1111/j.1524-475x.2007.00278.x.Suche in Google Scholar

13. Hong, W. X.; Hu, M. S.; Esquivel, M.; Liang, G. Y.; Rennert, R. C.; McArdle, A. The Role of Hypoxia-Inducible Factor in Wound Healing. Adv. Wound Care 2014, 3 (5), 390–399; https://doi.org/10.1089/wound.2013.0520.Suche in Google Scholar PubMed PubMed Central

14. Yan, L.; Colandrea, V. J.; Hale, J. J. Prolyl Hydroxylase Domain-Containing Protein Inhibitors as Stabilizers of Hypoxia-Inducible Factor: Small Molecule-Based Therapeutics for Anemia. Expert Opin. Ther. Pat. 2010, 20 (9), 1219–1245; https://doi.org/10.1517/13543776.2010.510836.Suche in Google Scholar PubMed

15. Bernhardt, W. M.; Wiesener, M. S.; Scigalla, P.; Chou, J.; Schmieder, R. E.; Günzler, V. Inhibition of Prolyl Hydroxylases Increases Erythropoietin Production in ESRD. J. Am. Soc. Nephrol. 2010, 21 (12), 2151–2156; https://doi.org/10.1681/asn.2010010116.Suche in Google Scholar PubMed PubMed Central

16. Matsuura, H.; Ichiki, T.; Inoue, E.; Nomura, M.; Miyazaki, R.; Hashimoto, T. Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance. Circulation 2013, 127 (21), 2078–2087; https://doi.org/10.1161/circulationaha.113.001742.Suche in Google Scholar PubMed

17. Meneses, A. M.; Wielockx, B. PHD2: From Hypoxia Regulation to Disease Progression. Hypoxia 2016, 4, 53–67; https://doi.org/10.2147/hp.s53576.Suche in Google Scholar PubMed PubMed Central

18. Hong, Y. R.; Kim, H. T.; Lee, S. C.; Ro, S.; Cho, J. M.; Kim, I. S. [(4-Hydroxyl-Benzo [4, 5] Thieno [3, 2-c] Pyridine-3-Carbonyl)-Amino]-Acetic Acid Derivatives; HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues. Bioorg. Med. Chem. Lett 2013, 23 (21), 5953–5957; https://doi.org/10.1016/j.bmcl.2013.08.067.Suche in Google Scholar PubMed

19. Su, K.; Li, Z.; Yu, Y.; Zhang, X. The Prolyl Hydroxylase Inhibitor Roxadustat: Paradigm in Drug Discovery and Prospects for Clinical Application Beyond Anemia. Drug Discov. Today 2020, 25 (7), 1262–1269; https://doi.org/10.1016/j.drudis.2020.04.017.Suche in Google Scholar PubMed

20. Yeh, T. L.; Leissing, T.; Abboud, M. I.; Thinnes, C. C.; Atasoylu, O.; Holt-Martyn, J. P. Molecular and Cellular Mechanisms of Hif Prolyl Hydroxylase Inhibitors in Clinical Trials. Chem. Sci. 2017, 8 (11), 7651–7668; https://doi.org/10.1039/c7sc02103h.Suche in Google Scholar PubMed PubMed Central

21. Chan, M. C.; Atasoylu, O.; Hodson, E.; Tumber, A.; Leung, I. K. H.; Chowdhury, R. Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain. PLoS One 2015, 10 (7), e0132004; https://doi.org/10.1371/journal.pone.0132004.Suche in Google Scholar PubMed PubMed Central

22. Figg, W. D.Jr; McDonough, M. A.; Chowdhury, R.; Nakashima, Y.; Zhang, Z.; Holt-Martyn, J. P. Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat. ChemMedChem 2021, 16 (13), 2082–2088; https://doi.org/10.1002/cmdc.202100133.Suche in Google Scholar PubMed PubMed Central

23. Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B. Copper (I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates. J. Am. Chem. Soc. 2005, 127 (1), 210–216; https://doi.org/10.1021/ja0471525.Suche in Google Scholar PubMed

24. Kawamura, A.; Tumber, A.; Rose, N. R.; King, O. N.; Daniel, M.; Oppermann, U. Development of Homogeneous Luminescence Assays for Histone Demethylase Catalysis and Binding. Anal. Biochem. 2010, 404 (1), 86–93; https://doi.org/10.1016/j.ab.2010.04.030.Suche in Google Scholar PubMed PubMed Central

25. Arsenault, P. R.; Song, D.; Bergkamp, M.; Ravaschiere, A. M.; Navalsky, B. E.; Lieberman, P. M. Identification of Small-Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor. ChemBioChem 2016, 17 (24), 2316–2323; https://doi.org/10.1002/cbic.201600493.Suche in Google Scholar PubMed PubMed Central

26. Kim, S. Y.; Yang, E. G. Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and their Therapeutic Implications. Molecules 2015, 20 (11), 20551–20568; https://doi.org/10.3390/molecules201119717.Suche in Google Scholar PubMed PubMed Central

27. Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S. AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. J. Comput. Chem. 2009, 30 (16), 2785–2791; https://doi.org/10.1002/jcc.21256.Suche in Google Scholar PubMed PubMed Central

28. Bikadi, Z.; Hazai, E. Application of the PM6 Semi-Empirical Method to Modeling Proteins Enhances Docking Accuracy of AutoDock. J. Cheminf. 2009, 1, 1–16; https://doi.org/10.1186/1758-2946-1-15.Suche in Google Scholar PubMed PubMed Central

29. Seeliger, D.; De Groot, B. L. Ligand Docking and Binding Site Analysis with PyMOL and Autodock/Vina. J. Comput. Aided Mol. Des. 2010, 24 (5), 417–422; https://doi.org/10.1007/s10822-010-9352-6.Suche in Google Scholar PubMed PubMed Central

30. Sayaf, A. M.; Ahmad, H.; Aslam, M. A.; Ghani, S. A.; Bano, S.; Yousafi, Q. Pharmacotherapeutic Potential of Natural Products to Target the SARS-CoV-2 PLpro Using Molecular Screening and Simulation Approaches. Appl. Biochem. Biotechnol. 2023, 195, 1–20; https://doi.org/10.1007/s12010-023-04466-1.Suche in Google Scholar PubMed PubMed Central

31. Case, D. A.; Cheatham, T. E.III; Darden, T.; Gohlke, H.; Luo, R.; Merz, K. M.Jr. The Amber Biomolecular Simulation Programs. J. Comput. Chem. 2005, 26 (16), 1668–1688; https://doi.org/10.1002/jcc.20290.Suche in Google Scholar PubMed PubMed Central

32. Salomon-Ferrer, R.; Case, D. A.; Walker, R. C. An Overview of the Amber Biomolecular Simulation Package. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2013, 3 (2), 198–210; https://doi.org/10.1002/wcms.1121.Suche in Google Scholar

33. Wang, J. Antechamber: An Accessory Software Package for Molecular Mechanical Calculations. J. Am. Chem. Soc. 2001, 222 (1).Suche in Google Scholar

34. Khan, A.; Randhawa, A. W.; Balouch, A. R.; Mukhtar, N.; Sayaf, A. M.; Suleman, M. Blocking Key Mutated Hotspot Residues in the RBD of the Omicron Variant (B. 1.1. 529) with Medicinal Compounds to Disrupt the RBD-hACE2 Complex using Molecular Screening and Simulation Approaches. RSC Adv. 2022, 12 (12), 7318–7327; https://doi.org/10.1039/d2ra00277a.Suche in Google Scholar PubMed PubMed Central

35. Mishra, S. K.; Koča, J. Assessing the Performance of MM/PBSA, MM/GBSA, and QM–MM/GBSA Approaches on Protein/Carbohydrate Complexes: Effect of Implicit Solvent Models, QM Methods, and Entropic Contributions. J. Phys. Chem. B 2018, 122 (34), 8113–8121; https://doi.org/10.1021/acs.jpcb.8b03655.Suche in Google Scholar PubMed

36. Pérez, A. J. Tracking of Bacterial Metabolism with Azidated Precursors and Click-Chemistry; Johann Wolfgang Goethe-Univ., Diss., 2016: Frankfurt am Main, 2015.Suche in Google Scholar

37. Tornøe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on Solid Phase:[1, 2, 3]-Triazoles by Regiospecific Copper (I)-Catalyzed 1, 3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 2002, 67 (9), 3057–3064; https://doi.org/10.1021/jo011148j.Suche in Google Scholar PubMed

38. Hou, J.; Liu, X.; Shen, J.; Zhao, G.; Wang, P. G. The Impact of Click Chemistry in Medicinal Chemistry. Expet Opin. Drug Discov. 2012, 7 (6), 489–501; https://doi.org/10.1517/17460441.2012.682725.Suche in Google Scholar PubMed

39. Cholko, T.; Chen, W.; Tang, Z.; Chang, C. E. A. A Molecular Dynamics Investigation of CDK8/CycC and Ligand Binding: Conformational Flexibility and Implication in Drug Discovery. J. Comput. Aided Mol. Des. 2018, 32, 671–685; https://doi.org/10.1007/s10822-018-0120-3.Suche in Google Scholar PubMed PubMed Central

40. Erijman, A.; Rosenthal, E.; Shifman, J. M. How Structure Defines Affinity in Protein-Protein Interactions. PLOS one 2014, 9 (10), e110085; https://doi.org/10.1371/journal.pone.0110085.Suche in Google Scholar PubMed PubMed Central

41. Bronowska, A. K. Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design. In Thermodynamics-Interaction Studies-Solids, Liquids and Gases; IntechOpen: London, UK, 2011.Suche in Google Scholar

42. Huang, S. Y.; Zou, X. Advances and Challenges in Protein-Ligand Docking. Int. J. Mol. Sci. 2010, 11 (8), 3016–3034; https://doi.org/10.3390/ijms11083016.Suche in Google Scholar PubMed PubMed Central

43. Grinter, S. Z.; Zou, X. Challenges, Applications, and Recent Advances of Protein-Ligand Docking in Structure-Based Drug Design. Molecules 2014, 19 (7), 10150–10176; https://doi.org/10.3390/molecules190710150.Suche in Google Scholar PubMed PubMed Central

44. Antunes, D. A.; Devaurs, D.; Kavraki, L. E. Understanding the Challenges of Protein Flexibility in Drug Design. Expet Opin. Drug Discov. 2015, 10 (12), 1301–1313; https://doi.org/10.1517/17460441.2015.1094458.Suche in Google Scholar PubMed

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/pac-2024-0301).

Published Online: 2025-03-06
Published in Print: 2025-06-26

© 2025 IUPAC & De Gruyter

Artikel in diesem Heft

  1. Frontmatter
  2. In this issue
  3. Preface
  4. Preface: 9th International Conference for Young Chemists (ICYC) 2024
  5. Research Articles
  6. Doping TiO2 with Cu from electroplating wastewater for remarkable improvement of its activity under visible light for E. coli bacterial disinfection in water
  7. Investigating the potential of prenylated and geranylated acylphloroglucinol-based xanthenones as potent soybean 15-lipoxygenase inhibitors: a combined in vitro and in silico approach
  8. Intelligent food packaging from Ganyong starch (Canna Edulis Kerr.) modified with nanocellulose from corn husk (Zea mays) and curcumin as bioindicator
  9. Evaluation of 2-(1H-1,2,3-triazol-1-yl) acetic acid derivatives as potential human hypoxia-inducible factor (HIF) prolyl hydroxylase domain-2 (PHD2) inhibitors
  10. Microparticles zerumbone from Zingiber zerumbet rhizome in chitosan modified oleic acid
  11. Enhanced visible photocatalytic degradation of diclofenac by ultrasound-assisted prepared C and N co-doping TiO2
  12. Enhanced stability and permeability of graphene oxide nanocomposite membranes via glycine and diglycine cross-linking
  13. Furanyl-Chalcones as antimalarial agent: synthesis, in vitro study, DFT, and docking analysis of PfDHFR inhibition
https://doi.org/10.1515/pac-2024-0301
Schlagwörter für diesen Artikel
1,2,3-triazole; HIF; hypoxia-inducible factor; ICYC 2024; PHD inhibitors; prolyl hydroxylase domain

Artikel in diesem Heft

  1. Frontmatter
  2. In this issue
  3. Preface
  4. Preface: 9th International Conference for Young Chemists (ICYC) 2024
  5. Research Articles
  6. Doping TiO2 with Cu from electroplating wastewater for remarkable improvement of its activity under visible light for E. coli bacterial disinfection in water
  7. Investigating the potential of prenylated and geranylated acylphloroglucinol-based xanthenones as potent soybean 15-lipoxygenase inhibitors: a combined in vitro and in silico approach
  8. Intelligent food packaging from Ganyong starch (Canna Edulis Kerr.) modified with nanocellulose from corn husk (Zea mays) and curcumin as bioindicator
  9. Evaluation of 2-(1H-1,2,3-triazol-1-yl) acetic acid derivatives as potential human hypoxia-inducible factor (HIF) prolyl hydroxylase domain-2 (PHD2) inhibitors
  10. Microparticles zerumbone from Zingiber zerumbet rhizome in chitosan modified oleic acid
  11. Enhanced visible photocatalytic degradation of diclofenac by ultrasound-assisted prepared C and N co-doping TiO2
  12. Enhanced stability and permeability of graphene oxide nanocomposite membranes via glycine and diglycine cross-linking
  13. Furanyl-Chalcones as antimalarial agent: synthesis, in vitro study, DFT, and docking analysis of PfDHFR inhibition
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