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New thymol-derived triazole exhibits promising activity against Trichophyton rubrum

  • Clinical Microbiology - Research Paper
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Abstract

Fungal infections have emerged worldwide, and azole antifungals are widely used to control these infections. However, the emergence of antifungal resistance has been compromising the effectiveness of these drugs. Therefore, the objective of this study was to evaluate the antifungal and cytotoxic activities of the nine new 1,2,3 triazole compounds derived from thymol that were synthesized through Click chemistry. The binding mode prediction was carried out by docking studies using the crystallographic structure of Lanosterol 14α-demethylase G73E mutant from Saccharomyces cerevisiae. The new compounds showed potent antifungal activity against Trichophyton rubrum but did not show relevant action against Aspergillus fumigatus and Candida albicans. For T. rubrum, molecules nº 5 and 8 showed promising results, emphasizing nº 8, whose fungicidal and fungistatic effects were similar to fluconazole. In addition, molecule nº 8 showed low toxicity for keratinocytes and fibroblasts, concluding that this compound demonstrates promising characteristics for developing a new drug for dermatophytosis caused by T. rubrum, or serves as a structural basis for further research.

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References

  1. Miceli MH, Díaz JA, Lee SA (2011) Emerging opportunistic yeast infections. Lancet Infect Dis 11:142–151. https://doi.org/10.1016/S1473-3099(10)70218-8

    Article  PubMed  Google Scholar 

  2. Wu S, Wang Y, Liu N, Dong G, Sheng C (2017) Tackling fungal resistance by biofilm inhibitors. J Med Chem 60:2193–2211. https://doi.org/10.1021/acs.jmedchem.6b01203

    Article  CAS  PubMed  Google Scholar 

  3. Carmona EM, Limper AH (2017) Overview of treatment approaches for fungal infections. Clin Chest Med 38:393–402. https://doi.org/10.1016/j.ccm.2017.04.003

    Article  PubMed  Google Scholar 

  4. Groll AH, Lumb J (2012) New developments in invasive fungal disease. Future Microbiol 7:179–184. https://doi.org/10.2217/fmb.11.154

    Article  PubMed  Google Scholar 

  5. Almeida F, Rodrigues ML, Coelho C (2019) The still underestimated problem of fungal diseases worldwide. Front Microbiol 10:1–5. https://doi.org/10.3389/fmicb.2019.00214

    Article  Google Scholar 

  6. Munzen ME, Goncalves Garcia AD, Martinez LR (2023) An update on the global treatment of invasive fungal infections. Future Microbiol 18:1095–1117. https://doi.org/10.2217/fmb-2022-0269

    Article  CAS  PubMed  Google Scholar 

  7. Peixoto I, Maquine G, Francesconi VA, Francesconi F (2010) Dermatophytosis caused by Tricophyton rubrum as an opportunistic infection in patients with Cushing disease. An Bras Dermatol 85:888–890

    Article  PubMed  Google Scholar 

  8. Huang C, Peng Y, Zhang Y, Li R, Wan Z, Wang X (2019) Deep dermatophytosis caused by Trichophyton rubrum. Lancet Infect Dis 19:1380. https://doi.org/10.1016/S1473-3099(19)30551-1

    Article  PubMed  Google Scholar 

  9. Burmester A, Hipler UC, Uhrlaß S, Nenoff P, Singal A, Verma SB, Elsner P, Wiegand C (2020) Indian Trichophyton mentagrophytes squalene epoxidase erg1 double mutants show high proportion of combined fluconazole and terbinafine resistance. Mycoses 63:1175–1180. https://doi.org/10.1111/myc.13150

    Article  CAS  PubMed  Google Scholar 

  10. Bouchara JP, Mignon B, Chaturvedi V (2017) Dermatophytes and dermatophytoses: a thematic overview of state of the art, and the directions for future research and developments. Mycopathologia 182:1–4. https://doi.org/10.1007/s11046-017-0114-z

    Article  CAS  PubMed  Google Scholar 

  11. Arikan S, Rex J H (2001) Nystatin LF (Aronex/Abbott). Current opinion in investigational drugs (London, England: 2000) 2:488–495

  12. Allen D, Wilson D, Drew R, Perfect J (2015) Azole antifungals: 35 years of invasive fungal infection management. Expert Rev Anti Infect Ther 13:787–798. https://doi.org/10.1586/14787210.2015.1032939

    Article  CAS  PubMed  Google Scholar 

  13. Denning DW (2003) Echinocandin antifungal drugs. Lancet 362:1142–1151. https://doi.org/10.1016/S0140-6736(03)14472-8

    Article  CAS  PubMed  Google Scholar 

  14. Moudgal V, Sobel J (2010) Antifungals to treat Candida albicans. Expert Opin Pharmacother 11:2037–2048. https://doi.org/10.1517/14656566.2010.493875

    Article  CAS  PubMed  Google Scholar 

  15. Bhatia A, Kanish B, Badyal D, Kate P (2019) Efficacy of oral terbinafine versus itraconazole in treatment of dermatophytic infection of skin—A prospective, randomized comparative study. Indian J Pharmacol 51:116–119. https://doi.org/10.1016/B978-0-323-60984-5.00062-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Roemer T, Krysan DJ (2014) Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a019703

    Article  PubMed  PubMed Central  Google Scholar 

  17. Monk BC, Sagatova AA, Hosseini P, Ruma YN, Wilson RK, Keniya MV (2019) Fungal Lanosterol 14α-demethylase: A target for next-generation antifungal design. Biochim Biophys Acta Proteins Proteom. https://doi.org/10.1016/j.bbapap.2019.02.008

    Article  PubMed  Google Scholar 

  18. Yin W, Zhang Y, Cui H, Jiang H, Liu L, Zheng Y, Wu T, Zhao L, Sun Y, Su X, Li S, Zhao D, Cheng M (2021) Design, synthesis and evaluation of novel 5-phenylthiophene derivatives as potent fungicidal of Candida albicans and antifungal reagents of fluconazole-resistant fungi. Eur J Med Chem 225:113740. https://doi.org/10.1016/j.ejmech.2021.113740

    Article  CAS  PubMed  Google Scholar 

  19. Zhao L, Sun Y, Yin W, Tian L, Sun N, Zheng Y, Zhang C, Zhao S, Su X, Zhao D, Cheng M (2022) Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broad-spectrum antifungal agents. Eur J Med Chem 228:113987. https://doi.org/10.1016/j.ejmech.2021.113987

    Article  CAS  PubMed  Google Scholar 

  20. Thamban Chandrika N, Shrestha SK, Ngo HX, Tsodikov OV, Howard KC, Garneau-Tsodikova S (2018) Alkylated piperazines and piperazine-azole hybrids as antifungal agents. J Med Chem 61:158–173. https://doi.org/10.1021/acs.jmedchem.7b01138

    Article  CAS  PubMed  Google Scholar 

  21. Liu N, Tu J, Dong G, Wang Y, Sheng C (2018) Emerging new targets for the treatment of resistant fungal infections. J Med Chem 61:5484–5511. https://doi.org/10.1021/acs.jmedchem.7b01413

    Article  CAS  PubMed  Google Scholar 

  22. Corrêa JCR, Salgado HRN (2011) Review of fluconazole properties and analytical methods for its determination. Crit Rev Anal Chem 41:124–132. https://doi.org/10.1080/10408347.2011.557980

    Article  CAS  Google Scholar 

  23. Fisher MC, Hawkins NJ, Sanglard D, Gurr SJ (2018) Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science 360:739–742. https://doi.org/10.1126/science.aap7999

    Article  CAS  PubMed  Google Scholar 

  24. Agnello S, Brand M, Chellat MF, Gazzola S, Riedl R (2019) A structural view on medicinal chemistry strategies against drug resistance. Angew Chem Int Ed Engl 58:3300–3345. https://doi.org/10.1002/anie.201802416

    Article  CAS  PubMed  Google Scholar 

  25. Han G, Liu N, Li C, Tu J, Li Z, Sheng C (2020) Discovery of novel fungal lanosterol 14α-demethylase (CYP51)/histone deacetylase dual inhibitors to treat azole-resistant candidiasis. J Med Chem 63:5341–5359. https://doi.org/10.1021/acs.jmedchem.0c00102

    Article  CAS  PubMed  Google Scholar 

  26. Da X, Nishiyama Y, Tie D, Hein KZ, Yamamoto O, Morita E (2019) Antifungal activity and mechanism of action of Ou-gon (Scutellaria root extract) components against pathogenic fungi. Sci Rep 9:1683. https://doi.org/10.1038/s41598-019-38916-w

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Arif T, Bhosale JD, Kumar N, Mandal TK, Bendre RS, Lavekar GS, Dabur R (2009) Natural products–antifungal agents derived from plants. J Asian Nat Prod Res 11:621–638. https://doi.org/10.1080/10286020902942350

    Article  CAS  PubMed  Google Scholar 

  28. Guo N, Liu J, Wu X, Bi X, Meng R, Wang X, Xiang H, Deng X, Yu L (2009) Antifungal activity of thymol against clinical isolates of fluconazole-sensitive and -resistant Candida albicans. J Med Microbiol 58:1074–1079. https://doi.org/10.1099/jmm.0.008052-0

    Article  CAS  PubMed  Google Scholar 

  29. Zhao J, Li Y, Liu Q, Gao K (2010) Antimicrobial activities of some thymol derivatives from the roots of Inula hupehensis. Food Chem 120:512–516. https://doi.org/10.1016/j.foodchem.2009.10.045

    Article  CAS  Google Scholar 

  30. Tyndall JDA, Sabherwal M, Sagatova AA, Keniya MV, Negroni J, Wilson RK, Woods MA, Tietjen K, Monk BC (2016) Structural and functional elucidation of yeast lanosterol 14α-demethylase in complex with agrochemical antifungals. PLoS One 11:e0167485. https://doi.org/10.1371/journal.pone.0167485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Alves Eloy M, Ribeiro R, Martins Meireles L, Antonio De Sousa Cutrim T, Santana Francisco C, LirianJavarini C, Borges WDS, Costa AV, De Queiroz VT, Scherer R, Lacerda V, Alves BezerraMorais P (2021) Thymol as an interesting building block for promising fungicides against fusarium solani. J Agric Food Chem 69:6958–6967. https://doi.org/10.1021/acs.jafc.0c07439

    Article  CAS  PubMed  Google Scholar 

  32. Clinical and Laboratory Standards Institute (2008) Reference method for broth dilution antifungal susceptibility testing of yeast; approved standard—3rd ed. CLSI document M27–3A. Clinical and Laboratory Standards Institute, Wayne, PA.

  33. Clinical and Laboratory Standards Institute (2008) Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard, 2nd ed CLSI M38-A2 Clinical and Laboratory Standards Institute, Wayne, PA.

  34. Espinel-Ingroff A, Fothergil A, Peter J, Rinaldi M, Walsh T (2002) Testing conditions for determination of minimum fungicidal concentrations of new and established antifungal agents for, society. 40:3204–3208. https://doi.org/10.1128/JCM.40.9.3204

  35. Van Dijck P, Sjollema J, Camue BPA, Lagrou K, Berman J, D’Enfert C, Andes DR, Arendrup MC, Brakhage AA, Calderone R, Cantón E, Coenye T, Cos P, Cowen LE, Edgerton M, Espinel-Ingroff A, Filler SG, Ghannoum M, Gow NAR, Haas H, Jabra-Rizk MA, Johnson EM, Lockhart SR, Lopez-Ribot JL, Maertens J, Munro CA, Nett JE, Nobile CJ, Pfaller MA, Ramage G, Sanglard D, Sanguinetti M, Spriet I, Verweij PE, Warris A, Wauters J, Yeaman MR, Zaat SAJ, Thevissen K (2018) Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms. Microbial Cell 5:300–326. https://doi.org/10.15698/mic2018.07.638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Klepser ME, Ernst EJ, Lewis RE, Ernst ME, Pfaller MA (1998) Influence of test conditions on antifungal time-kill curve results: Proposal for standardized methods. Antimicrob Agents Chemother 42:1207–1212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ghannoum M, Isham N, Verma A, Plaum S, Fleischer A, Hardas B (2013) In vitro antifungal activity of naftifine hydrochloride against dermatophytes. Antimicrob Agents Chemother 57:4369–4372. https://doi.org/10.1128/AAC.01084-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 16:55–63

    Article  Google Scholar 

  39. Kumar S, Sharma B, Mehra V, Kumar V (2021) Recent accomplishments on the synthetic/biological facets of pharmacologically active 1H–1,2,3-triazoles. Eur J Med Chem 212:1–32. https://doi.org/10.1016/j.ejmech.2020.113069

    Article  CAS  Google Scholar 

  40. Teng X, Wang Y, Gu J, Shi P, Shen Z, Ye L (2018) Antifungal agents: Design, synthesis, antifungal activity and molecular docking of phloroglucinol derivatives. Molecules 23. https://doi.org/10.3390/molecules23123116

  41. Resende DISP, Pereira-Terra P, Inácio ÂS, Da Costa PM, Pinto E, Sousa E, Pinto MMM (2018) Lichen xanthones as models for new antifungal agents. Molecules 23. https://doi.org/10.3390/molecules23102617

  42. Magagnin CM, Stopiglia CD, Vieira FJ, Heidrich D, Machado M, Vetoratto G, Lamb FM, Scroferneker ML (2011) Antifungal susceptibility of dermatophytes isolated from patients with chronic renal failure. An Bras Dermatol 86(4):694–701. https://doi.org/10.1590/s0365-05962011000400011

  43. Ni T, Pang L, Cai Z, Xie F, Ding Z, Hao Y, Li R, Yu S, Chai X, Wang T, Jin Y, Zhang D, Jiang Y (2018) Design, synthesis, and in vitro antifungal evaluation of novel triazole derivatives bearing alkynyl side chains. J Saudi Chem Soc. https://doi.org/10.1016/j.jscs.2018.10.003

    Article  Google Scholar 

  44. Allahdadi M, Hajihossein R, Kord M, Rahmati E, Amanloo S, Didehdar M (2019) Molecular characterization and antifungal susceptibility profile of dermatophytes isolated from scalp dermatophyte carriage in primary school children in Arak city, Center of Iran. J Mycol Med. https://doi.org/10.1016/j.mycmed.2019.01.002

    Article  PubMed  Google Scholar 

  45. Wiederhold NP (2022) Pharmacodynamics, mechanisms of action and resistance, and spectrum of activity of new antifungal agents. J Fungi 8. https://doi.org/10.3390/jof8080857

  46. Harrison JR, Brand S, Smith V, Robinson DA, Thompson S, Smith A, Davies K, Mok N, Torrie LS, Collie I, Hallyburton I, Norval S, Simeons FRC, Stojanovski L, Frearson JA, Brenk R, Wyatt PG, Gilbert IH, Read KD (2018) A molecular hybridization approach for the design of potent, highly selective, and brain-penetrant N-Myristoyltransferase inhibitors. J Med Chem 61:8374–8389. https://doi.org/10.1021/acs.jmedchem.8b00884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Iman M, Peroomian T, Davood A, Amini M, Sardari S, Azerang P (2016) Design, synthesis and evaluation of new azoles as antifungal agents: a molecular hybridization approach. Pharm Chem J 49:687–693. https://doi.org/10.1007/s11094-016-1354-9

    Article  CAS  Google Scholar 

  48. Nepali K, Lee H-Y, Liou J-P (2019) Nitro-group-containing drugs. J Med Chem 62:2851–2893. https://doi.org/10.1021/acs.jmedchem.8b00147

    Article  CAS  PubMed  Google Scholar 

  49. Benedetto Tiz D, Bagnoli L, Rosati O, Marini F, Sancineto L, Santi C (2022) New halogen-containing drugs approved by FDA in 2021: an overview on their syntheses and pharmaceutical use. Molecules 27:1643. https://doi.org/10.3390/molecules27051643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Curran MP, McCormack PL (2008) Methoxy polyethylene glycol-epoetin beta: a review of its use in the management of anaemia associated with chronic kidney disease. Drugs 68:1139–1156. https://doi.org/10.2165/00003495-200868080-00009

    Article  CAS  PubMed  Google Scholar 

  51. Nivoix Y, Ledoux MP, Herbrecht R (2020) Antifungal therapy: new and evolving therapies. Semin Respir Crit Care Med 41:158–174. https://doi.org/10.1055/s-0039-3400291

    Article  PubMed  Google Scholar 

  52. Öz Y, Özdemir HG, Gökbolat E, Kiraz N, Ilkit M, Seyedmousavi S (2016) Time-kill kinetics and in vitro antifungal susceptibility of non-fumigatus aspergillus species isolated from patients with ocular mycoses. Mycopathologia 181:225–233. https://doi.org/10.1007/s11046-015-9969-z

    Article  CAS  PubMed  Google Scholar 

  53. Kowalczyk A, Fecka I, Przychodna M, Sopata S, Bodalska A (2020) Thymol and thyme essential oil—new insights into selected therapeutic applications. Molecules 25:4125–4142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jafri H, Ahmad I (2020) Thymus vulgaris essential oil and thymol inhibit biofilms and interact synergistically with antifungal drugs against drug resistant strains of Candida albicans and Candida tropicalis. J Mycol Med 30:100911. https://doi.org/10.1016/j.mycmed.2019.100911

    Article  CAS  PubMed  Google Scholar 

  55. Khan MSA, Malik A, Ahmad I (2012) Anti-candidal activity of essential oils alone and in combination with amphotericin B or fluconazole against multi-drug resistant isolates of Candida albicans. Med Mycol 50:33–42. https://doi.org/10.3109/13693786.2011.582890

    Article  CAS  PubMed  Google Scholar 

  56. Adan A, Kiraz Y, Baran Y (2016) Cell proliferation and cytotoxicity assays. Curr Pharm Biotechnol 17:1213. https://doi.org/10.2174/1389201017666160808160513

    Article  CAS  PubMed  Google Scholar 

  57. Gupta AK, Lyons DCA (2015) The rise and fall of oral ketoconazole. J Cutan Med Surg 19:352–357. https://doi.org/10.1177/1203475415574970

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the Foundation for Support to Research and Innovation of Espírito Santo-FAPES. In addition, this study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES)—Finance Code 001.

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Authors and Affiliations

  1. Pharmaceutical Sciences Graduate Program, Universidade Vila Velha, Comissário José Dantas de Melo St., 21, Boa Vista, Vila Velha, Espírito Santo, 29102-770, Brazil

    Thiago Antonio de Sousa Cutrim, Leandra Martins Meireles, Marcio Fronza & Rodrigo Scherer

  2. Agrochemical Graduate Program, Federal University of Espírito Santo, Alegre, Espirito Santo, 29500-000, Brazil

    Mariana Alves Eloy, Lara Chaves de Freitas Ferreira & Pedro Alves Bezerra Morais

  3. Plant Biotechnology Graduate Program, Universidade Vila Velha, Vila Velha, Espírito Santo, 29102-770, Brazil

    Fernando Fontes Barcelos

  4. Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    Tatiana Alves Reis

  5. Center for Research in Medical Mycology, Department of Pathology, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil

    Sarah Santos Gonçalves

  6. Chemistry Graduate Program, Universidade Federal Do Espírito Santo, Vitória, Espírito Santo, Brazil

    Valdemar Lacerda Jr.

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  1. Thiago Antonio de Sousa Cutrim
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de Sousa Cutrim, T.A., Eloy, M.A., Barcelos, F.F. et al. New thymol-derived triazole exhibits promising activity against Trichophyton rubrum. Braz J Microbiol (2024). https://doi.org/10.1007/s42770-024-01295-0

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