Skip to content
2000
image of Discovery of Furan-tethered Triazolothiadiazoles and Triazolothia- diazines as Potent Tyrosinase Inhibitors for the Treatment of Skin Diseases: Insights from Kinetics Data and Computational Modeling

Abstract

Introduction

Tyrosinase, a copper-containing enzyme, is responsible for melanin production, and its overactivity can lead to hyperpigmentation.

Methods

This study aimed to evaluate triazolothiadiazoles (, ) and triazolothiadiazines () against human and mushroom tyrosinase isozymes.

Results

Several derivatives, such as , , , , and were identified as potent and selective inhibitors of mushroom tyrosinase, with IC values ranging from 1.9 to 15.2 µM. Similarly, compounds , , , and effectively inhibited human tyrosinase, with IC values between 12.6 and 18.5 µM. Mechanism-based studies revealed that these active compounds exhibited competitive inhibition against both isozymes without any cytotoxic effects. analysis further demonstrated that these compounds fit well into the active site of both tyrosinase isozymes.

Conclusion

Additionally, the pharmacokinetic profile of these compounds highlighted promising drug-like properties, making them potential candidates for the development of effective therapeutics for skin disorders.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673349818250302105830
2025-08-06
2025-11-04

  • From This Site

    /content/journals/cmc/10.2174/0109298673349818250302105830
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Del Bino S. Duval C. Bernerd F. Clinical and biological characterization of skin pigmentation diversity and its consequences on UV impact. Int. J. Mol. Sci. 2018 19 9 2668 10.3390/ijms19092668 30205563
    [Google Scholar]
  2. Thappa D. MELASMA (CHLOASMA). Indian J. Dermatol. 2004 49 4 165 176
    [Google Scholar]
  3. Benito-Martínez S. Salavessa L. Raposo G. Marks M.S. Delevoye C. Melanin transfer and fate within keratinocytes in human skin pigmentation. Integr. Comp. Biol. 2021 61 4 1546 1555 10.1093/icb/icab094 34021340
    [Google Scholar]
  4. Kanteev M. Goldfeder M. Fishman A. Structure–function correlations in tyrosinases. Protein Sci. 2015 24 9 1360 1369 10.1002/pro.2734 26104241
    [Google Scholar]
  5. Lee, S.Y.; Baek, N.; Nam, T-G. Natural, semisynthetic and synthetic tyrosinase inhibitors. J. Enzyme. Inhib. Med. Chem. 2016 31 1 1 13 10.3109/14756366.2015.1004058 2568308
    [Google Scholar]
  6. Ramsden C.A. Riley P.A. Tyrosinase: The four oxidation states of the active site and their relevance to enzymatic activation, oxidation and inactivation. Bioorg. Med. Chem. 2014 22 8 2388 2395 10.1016/j.bmc.2014.02.048 24656803
    [Google Scholar]
  7. Cui H.-X. Duan F.F. Jia S.S. Antioxidant and tyrosinase inhibitory activities of seed oils from Torreya grandis Fort. ex Lindl. Biomed Res Int. 2018 2018 5314320 10.1155/2018/5314320.8
    [Google Scholar]
  8. Solano F. Melanins: skin pigments and much more-types, structural models, biological functions, and formation routes. New J. Sci. 2014 2014 1 28 10.1155/2014/498276
    [Google Scholar]
  9. Zolghadri S. Bahrami A. Khan M.T.H. Munoz-Munoz J. Garcia-Molina F. Garcia-Canovas F. Saboury A.A. A comprehensive review on tyrosinase inhibitors. J. Enzyme Inhib. Med. Chem. 2019 34 1 279 309 10.1080/14756366.2018.1545767 30734608
    [Google Scholar]
  10. Kim Y.J. Uyama H. Tyrosinase inhibitors from natural and synthetic sources: Structure, inhibition mechanism and perspective for the future. Cell. Mol. Life Sci. 2005 62 15 1707 1723 10.1007/s00018‑005‑5054‑y 15968468
    [Google Scholar]
  11. Zaidi K.U. Ali A.S. Ali S.A. Naaz I. Microbial tyrosinases: Promising enzymes for pharmaceutical, food bioprocessing, and environmental industry. Biochem Res Int. 2014 2014 854687 10.1155/2014/854687
    [Google Scholar]
  12. Khan M. Halim S.A. Shah L. Khan A. Ahmed I.E. Abdalla A.N. Jan A. Khalid A. Mushtaque A. Al-Harrasi A. Isoxazole analogues of dibenzazepine as possible leads against ulcers and skin disease: In vitro and in silico exploration. Saudi Pharm. J. 2023 31 12 101877 10.1016/j.jsps.2023.101877 38075546
    [Google Scholar]
  13. Souza P.M. Elias S.T. Simeoni L.A. de Paula J.E. Gomes S.M. Guerra E.N.S. Fonseca Y.M. Silva E.C. Silveira D. Magalhães P.O. Plants from Brazilian Cerrado with potent tyrosinase inhibitory activity. PLoS One 2012 7 11 e48589 10.1371/journal.pone.0048589 23173036
    [Google Scholar]
  14. Jablonski N.G. Chaplin G. Human skin pigmentation as an adaptation to UV radiation. Proc. Natl. Acad. Sci. USA 2010 107 Suppl 2 8962 8968 10.1073/pnas.0914628107 20445093
    [Google Scholar]
  15. Pillaiyar T. Manickam M. Namasivayam V. Skin whitening agents: Medicinal chemistry perspective of tyrosinase inhibitors. J. Enzyme Inhib. Med. Chem. 2017 32 1 403 425 10.1080/14756366.2016.1256882 28097901
    [Google Scholar]
  16. Carradori S. Şimşek R. Rešetar J. Melfi F. Tyrosinase enzyme and its inhibitors: An update of the literature. Metalloenzymes Academic Press 2024 533 546
    [Google Scholar]
  17. Espín J.C. Varón R. Fenoll L.G. Gilabert M.A. García-Ruíz P.A. Tudela J. García-Cánovas F. Kinetic characterization of the substrate specificity and mechanism of mushroom tyrosinase. Eur. J. Biochem. 2000 267 5 1270 1279 10.1046/j.1432‑1327.2000.01013.x 10691963
    [Google Scholar]
  18. Mann T. Gerwat W. Batzer J. Eggers K. Scherner C. Wenck H. Stäb F. Hearing V.J. Röhm K.H. Kolbe L. Inhibition of human tyrosinase requires molecular motifs distinctively different from mushroom tyrosinase. J. Invest. Dermatol. 2018 138 7 1601 1608 10.1016/j.jid.2018.01.019 29427586
    [Google Scholar]
  19. Roulier B. Pérès B. Haudecoeur R. Advances in the design of genuine human tyrosinase inhibitors for targeting melanogenesis and related pigmentations. J. Med. Chem. 2020 63 22 13428 13443 10.1021/acs.jmedchem.0c00994 32787103
    [Google Scholar]
  20. Palleschi C. Levin C. Alternative and natural treatments in dermatology. DNA 2024 19 21
    [Google Scholar]
  21. Kiruthika S. Sejal J. Keshavmurthy V. Cosmeceuticals in hyperpigmentary disorders. Pigment Int. 2023 10 1 14 23 10.4103/pigmentinternational.pigmentinternational_12_23
    [Google Scholar]
  22. Hu S. Laughter M.R. Anderson J.B. Sadeghpour M. Emerging topical therapies to treat pigmentary disorders: An evidence-based approach. J. Dermatolog. Treat. 2022 33 4 1931 1937 10.1080/09546634.2021.1940811 34114938
    [Google Scholar]
  23. Gupta O. Pradhan T. Chawla G. An updated review on diverse range of biological activities of 1,2,4-triazole derivatives: Insight into structure activity relationship. J. Mol. Struct. 2023 1274 134487 10.1016/j.molstruc.2022.134487
    [Google Scholar]
  24. Loganathan,C.G.; Krishnan, K.; Vachala, S.D.; Urolagin, D.; Vijayakumar, J. A review on 1,2,3 - triazole & piperazine derivatives with various biological activities. J. Pharm. Res. 2023 22 3 113 123 10.18579/jopcr/v22.3.23.43
    [Google Scholar]
  25. Patel V.M. Patel N.B. Chan-Bacab M.J. Rivera G. Synthesis, biological evaluation and molecular dynamics studies of 1,2,4-triazole clubbed mannich bases. Comput. Biol. Chem. 2018 76 264 274 10.1016/j.compbiolchem.2018.07.020 30092449
    [Google Scholar]
  26. Strzelecka M. Świątek P. 1, 2, 4-Triazoles as important antibacterial agents. Pharmaceuticals 2021 14 3 224 10.3390/ph14030224 33799936
    [Google Scholar]
  27. Dai J. Tian S. Yang X. Liu Z. Synthesis methods of 1,2,3-/1,2,4-triazoles: A review. Front Chem. 2022 10 891484 10.3389/fchem.2022.891484 36226121
    [Google Scholar]
  28. Rangaswamy V. Laddi U. A review on emerging impact of antitubercular activity of 1,2,4-triazole derivatives. Antiinfect. Agents 2024 22 1 e111023222113 10.2174/0122113525268198230921071016
    [Google Scholar]
  29. Bendi A. Yadav P. Saini K. Bhathiwal A.S. Raghav N. A comprehensive examination of heterocyclic scaffold chemistry for antitubercular activity. Chem. Biodivers. 2024 21 5 e202400067 10.1002/cbdv.202400067 38500408
    [Google Scholar]
  30. Somagond S.M. Novel 1, 2, 4-triazole clubbed with 1, 3, 4-oxadiazole motifs as efficient antimicrobial agents from N-arylsydnone as synthon. Indian J. Chem. 2022 61 10 1082 1096
    [Google Scholar]
  31. Ali Y.S. Design, Molecular docking study, synthesis and cytotoxicity evaluation of new 1, 3, 4-oxadiazole derivatives. Thesis, Republic of Iraq Ministry of Higher Education and Scientific Research Mustansiriyah University College of Pharmacy 2023
    [Google Scholar]
  32. Kumar S. Khokra S.L. Yadav A. Triazole analogues as potential pharmacological agents: A brief review. Future J. Pharm. Sci. 2021 7 1 106 10.1186/s43094‑021‑00241‑3 34056014
    [Google Scholar]
  33. Basappa V.C. Kameshwar V.H. Kumara K. Achutha D.K. Krishnappagowda L.N. Kariyappa A.K. Design and synthesis of coumarin-triazole hybrids: Biocompatible anti-diabetic agents, in silico molecular docking and ADME screening. Heliyon 2020 6 10 e05290 10.1016/j.heliyon.2020.e05290 33102875
    [Google Scholar]
  34. Azam M.A. Tripuraneni N.S. Selective phosphodiesterase 4B inhibitors: A review. Sci. Pharm. 2014 82 3 453 481 10.3797/scipharm.1404‑08 25853062
    [Google Scholar]
  35. Khan I. Hameed S. Al-Masoudi N.A. Abdul-Reda N.A. Simpson J. New triazolothiadiazole and triazolothiadiazine derivatives as kinesin Eg5 and HIV inhibitors: Synthesis, QSAR and modeling studies. Z. Naturforsch. B. J. Chem. Sci. 2015 70 1 47 58 10.1515/znb‑2014‑0162
    [Google Scholar]
  36. Mahalapbutr P. Sabuakham S. Nasoontorn S. Rungrotmongkol T. Silsirivanit A. Suriya U. Discovery of amphotericin B, an antifungal drug as tyrosinase inhibitor with potent anti-melanogenic activity. Int. J. Biol. Macromol. 2023 246 125587 10.1016/j.ijbiomac.2023.125587 37379954
    [Google Scholar]
  37. Ali A. Vijayan R. Dynamics of the ACE2–SARS-CoV-2/SARS-CoV spike protein interface reveal unique mechanisms. Sci. Rep. 2020 10 1 14214 10.1038/s41598‑020‑71188‑3 32848162
    [Google Scholar]
  38. Chemical Computing Group Inc Molecular operating environment (MOE). 2016 Available from: https://www.chemcomp.com/en/Products.htm
  39. 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 42717 10.1038/srep42717 28256516
    [Google Scholar]
  40. Koparır M. Cansız A. Demirdağ A. Synthesis of some new 4,5-substituted-4H-1,2,4-triazole-3-thiol derivatives. Molecules 2004 9 4 204 212 10.3390/90400204 18007424
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673349818250302105830
Loading
Discovery of Furan-tethered Triazolothiadiazoles and Triazolothia- diazines as Potent Tyrosinase Inhibitors for the Treatment of Skin Diseases: Insights from Kinetics Data and Computational Modeling
Bentham Science Publishers ; https://doi.org/10.2174/0109298673349818250302105830
/content/journals/cmc/10.2174/0109298673349818250302105830
/content/journals/cmc/10.2174/0109298673349818250302105830
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: melanin synthesis ; cytotoxicity ; molecular docking ; enzyme kinetics ; Tyrosinase inhibitors ; fused heterocycles

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