Naftoquinonas: Potencial biológico e perspectivas como antifúngicos
DOI:
https://doi.org/10.33448/rsd-v15i1.50492Palavras-chave:
Fungos patogênicos, Antifúngicos, Naftoquinonas, Mecanismos de ação.Resumo
As infecções fúngicas representam um problema crescente de saúde pública global, especialmente em razão do número limitado de classes de antifúngicos disponíveis, do surgimento de cepas multirresistentes e da elevada toxicidade associada às terapias atuais. Nesse cenário, as naftoquinonas têm despertado grande interesse como compostos bioativos promissores, apresentando ampla diversidade de atividades farmacológicas. Esta revisão apresenta uma análise abrangente da atividade antifúngica de naftoquinonas semissintéticas frente a diferentes fungos patogênicos de relevância clínica, como Candida spp., Cryptococcus spp., Aspergillus spp. e Sporothrix spp. São discutidas a diversidade química dessas moléculas, as modificações semissintéticas e as relações estrutura–atividade, destacando a influência da posição dos substituintes e das propriedades físico-químicas na eficácia antifúngica. Além disso, são abordados os principais mecanismos de ação propostos, como o ciclo redox, a geração de espécies reativas de oxigênio, a interação com a membrana fúngica, a desregulação do equilíbrio osmótico e a ligação covalente a alvos celulares. A toxicidade e a seletividade das naftoquinonas também são analisadas com base em estudos in vitro e in vivo. De modo geral, as naftoquinonas semissintéticas se mostram estruturas químicas promissoras para o desenvolvimento de novos antifúngicos, com potencial para superar a resistência fúngica e reduzir os efeitos adversos associados às drogas convencionais.
Referências
Ahmad, A., et al. (2008). Plumbagin-induced apoptosis of human breast cancer cells is mediated by inactivation of NF-κB and Bcl-2. Journal of Cellular Biochemistry, 105(6), 1461–1471.
Albuquerque Maranhão, F. C., et al. (2019). Mycoses in northeastern Brazil: Epidemiology and prevalence of fungal species. Brazilian Journal of Microbiology, 50(4), 969–978.
Allegra, S., et al. (2017). Pharmacokinetic evaluation of oral itraconazole for antifungal prophylaxis in children. Clinical and Experimental Pharmacology and Physiology, 44(11), 1083–1090.
Almeida, J. D. R et al (2024). Antifungal potential, mechanism of action, and toxicity of 1,4-naphthoquinone derivatives. European Journal of Microbiology and Immunology, 14 (2024) 3, 289–295.
Aminin, D., & Polonik, S. (2020). 1,4-Naphthoquinones: Some biological properties and applications. Chemical and Pharmaceutical Bulletin, 68(1), 46–57.
Babula, P., et al. (2009). Noteworthy secondary metabolites naphthoquinones: Their occurrence, pharmacological properties and analysis. Current Pharmaceutical Analysis, 5(1), 47–68.
Bentley, R., & Gatenbeck, S. (1965). Naphthoquinone biosynthesis in molds: The mechanism for formation of mollisin. Journal of the American Chemical Society, 87(10), 2205–2210.
Berkow, E. L., & Lockhart, S. R. (2018). Activity of CD101, a long-acting echinocandin, against clinical isolates of Candida auris. Diagnostic Microbiology and Infectious Disease, 90(3), 196–197.
Campoy, S., & Adrio, J. L. (2017). Antifungals. Biochemical Pharmacology, 133, 86–96.
Cavalcanti Chipoline, I., et al. (2020). Molecular mechanism of action of new 1,4-naphthoquinones tethered to 1,2,3-1H-triazoles with cytotoxic and selective effect against oral squamous cell carcinoma. Bioorganic Chemistry, 101, 103984.
Centers for Disease Control and Prevention. (2022). Candida auris. https://www.cdc.gov/fungal/candida-auris/
Chen, S. C. A., & Sorrell, T. C. (2017). Fluconazole. In Kucers’ the use of antibiotics: A clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs (7th ed., pp. 2756–2785). CRC Press.
Choudhari, D., et al. (2013). Synthesis and biological activity of imidazole-based 1,4-naphthoquinones. New Journal of Chemistry, 44(17), 6889–6901.
Damianakos, H., et al. (2012). Antimicrobial and cytotoxic isohexenylnaphthazarins from Arnebia euchroma. Molecules, 17(12), 14310–14322.
Dong, M., et al. (2017). Naphthoquinones from Onosma paniculatum with potential anti-inflammatory activity. Planta Medica, 83(7), 631–635.
Egu, S. A., et al. (2020). N-myristoyl transferase inhibitors with antifungal activity in quinolinequinone series. Communication in Physical Sciences, 5(4), 431–436.
Eisner, T., Rossini, C., & Eisner, M. (2000). Chemical defense of an earwig (Doru taeniatum). Chemoecology, 10(2), 81–87.
Fenandes, J. M. B., Vieira, L. T. & Castelhano, M. V. C. (2023). Revisão narrativa enquanto metodologia científica significativa: reflexões técnico-formativas. REDES – Revista Educacional da Sucesso. 3(1), 1-7. ISSN: 2763-6704.
Ferreira, M. do P. S. B. C., et al. (2014). Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi. Annals of Clinical Microbiology and Antimicrobials, 13(26).
Ferreira, P. G., et al. (2019). Synthesis, stability studies, and antifungal evaluation of substituted 2,3-dihydrofuranonaphthoquinones. Molecules, 24(5), 928.
Freire, C. P. V., et al. (2010). Synthesis and biological evaluation of substituted dihydrofuran naphthoquinones. MedChemComm, 1(3), 229–232.
Fontefria, A. M., et al. (2018). Antifungals discovery: New strategies to combat resistance. Letters in Applied Microbiology, 66(1), 2–13.
Furumoto, T. (2009). Biosynthetic origin of 2,3-epoxysesamone. Bioscience, Biotechnology, and Biochemistry, 73(11), 2535–2537.
Futuro, D. O., et al. (2018). The antifungal activity of naphthoquinones: An integrative review. Anais da Academia Brasileira de Ciências, 90(1), 1187–1214.
Galgiani, J. N., et al. (2016). IDSA clinical practice guideline for the treatment of coccidioidomycosis. Clinical Infectious Diseases, 63(6), e112–e146.
Gholampour, M., et al. (2020). Novel 2-amino-1,4-naphthoquinone hybrids. Bioorganic & Medicinal Chemistry, 28(21), 115718.
Gómez-Estrada, H., et al. (2012). Actividad antimalárica in vitro de Tabebuia billbergii. Revista Cubana de Plantas Medicinales, 17(2), 172–180.
Grela, E., et al. (2018). Imaging of human cells exposed to amphotericin B. Scientific Reports, 8, 14076.
Grela, E., et al. (2019). Modes of the antibiotic activity of amphotericin B. Scientific Reports, 9, 17029.
Gupta, A. K., Daigle, D., & Foley, K. A. (2015). Drug safety assessment of oral formulations of ketoconazole. Expert Opinion on Drug Safety, 14(2), 325–334.
Hook, I., Mills, C., & Sheridan, H. (2014). Bioactive naphthoquinones from higher plants. In Studies in Natural Products Chemistry (Vol. 41, pp. 119–160). Elsevier.
Hsu, Y. L., et al. (2006). Plumbagin induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation. Journal of Pharmacology and Experimental Therapeutics, 318(2), 484–494.
Hu, Z., et al. (2017). Recent advances in ergosterol biosynthesis and regulation mechanisms in Saccharomyces cerevisiae. Journal of Biosciences, 42(3), 493–504.
Hughes, L. M., et al. (2011). Design of anti-parasitic and anti-fungal hydroxy-naphthoquinones less susceptible to drug resistance. Molecular and Biochemical Parasitology, 177(1), 12–19.
Inbaraj, J. J., & Chignell, C. F. (2004). Cytotoxic action of juglone and plumbagin: A mechanistic study using HaCaT keratinocytes. Chemical Research in Toxicology, 17(1), 55–62.
Itzel López López, L., et al. (2014). Naftoquinonas: Propiedades biológicas y síntesis de lawsona y derivados. Vitae, 21(3), 248–258.
Jang, W. S., et al. (2017). Naphthofuroquinone derivatives show strong antimycobacterial activities. Journal of Chemotherapy, 29(6), 338–343.
Jentzsch, J., et al. (2020). New antiparasitic bis-naphthoquinone derivatives. Chemistry & Biodiversity, 17(2), e1900597.
Johnson, E. R., et al. (2010). Revealing noncovalent interactions. Journal of the American Chemical Society, 132(18), 6498–6506.
Ju Woo, H., et al. (2017). Anti-inflammatory action of CMEP-NQ suppresses TLR4 signaling pathways. Journal of Ethnopharmacology, 205, 103–115.
Kapadia, G. J., et al. (2017). Antiparasitic activity of menadione against Schistosoma mansoni. Acta Tropica, 167, 163–173.
Kawiak, A., Zawacka-Pankau, J., & Lojkowska, E. (2012). Plumbagin induces apoptosis in Her2-overexpressing breast cancer cells. Journal of Natural Products, 75(4), 747–751.
Khan, M. I. H., et al. (2016). Cytotoxic and antibacterial naphthoquinones from an endophytic fungus. Toxicology Reports, 3, 861–865.
Kim, G., & Lee, S. E. (2020). Antifungal and antiaflatoxigenic properties of naphthoquinones. Food Control, 119, 107506.
Kuck, D., et al. (2010). Nanaomycin A selectively inhibits DNMT3B. Molecular Cancer Therapeutics, 9(11), 3015–3023.
Kuete, V., et al. (2017). Cytotoxicity and mode of action of a naturally occurring naphthoquinone. Phytomedicine, 33, 62–68.
Kumagai, Y., et al. (2012). The chemical biology of naphthoquinones. Annual Review of Pharmacology and Toxicology, 52, 221–247.
Kurn, H., & Wadhwa, R. (2020). Itraconazole. StatPearls Publishing.
Leading International Fungal Education. (2017). The burden of fungal disease: New evidence to show the scale of the problem across the globe. http://www.life-worldwide.org/media-centre/article/the-burden-of-fungal-disease-new-evidence-to-show-the-scale-of-the-problem
Leyva, E., López, L. I., & García de la Cruz, R. F. (2017). Importancia química y biológica de las naftoquinonas: Revisión bibliográfica. Afinidad. https://www.raco.cat/index.php/afinidad/article/view/320755
Li, H., et al. (2018). Antimycobacterial 1,4-naphthoquinone natural products from Moneses uniflora. Phytochemistry Letters, 27, 229–233.
Liu, D., et al. (2020). Fetal outcomes after maternal exposure to oral antifungal agents during pregnancy: A systematic review and meta-analysis. International Journal of Gynecology & Obstetrics.
Liu, H., et al. (2020). Naphthoquinone derivatives with anti-inflammatory activity from mangrove-derived endophytic fungus Talaromyces sp. SK-S009. Molecules, 25(3), 576.
Lockhart, S. R. (2019). Candida auris and multidrug resistance: Defining the new normal. Academic Press.
Lomba, L. A., et al. (2017). A naphthoquinone from Sinningia canescens inhibits inflammation and fever in mice. Inflammation, 40(3), 1051–1061.
López, L. I., Leyva, E., & García de la Cruz, R. F. (2011). Naftoquinonas: Más do que pigmentos naturais. Revista Mexicana de Ciencias Farmacéuticas, 42(1), 6–17.
Mahal, K., et al. (2017). Improved anticancer and antiparasitic activity of new lawsone Mannich bases. European Journal of Medicinal Chemistry, 126, 421–431.
Mahoney, N., Molyneux, R. J., & Campbell, B. C. (2000). Regulation of aflatoxin production by naphthoquinones of walnut (Juglans regia). Journal of Agricultural and Food Chemistry, 48(9), 4418–4421.
Manickam, M., et al. (2018). Investigation of chemical reactivity of 2-alkoxy-1,4-naphthoquinones and their anticancer activity. Bioorganic & Medicinal Chemistry Letters, 28(11), 2023–2028.
Moraes, D. C., et al. (2018). β-Lapachone and α-nor-lapachone modulate Candida albicans viability and virulence factors. Journal de Mycologie Médicale, 28(2), 314–319.
Nature Microbiology. (2017). Stop neglecting fungi. Nature Microbiology, 2, 17120.
Nematollahi, A., Aminimoghadamfarouj, N., & Wiart, C. (2012). Reviews on 1,4-naphthoquinones from Diospyros L. Pharmaceutical Biology, 50(3), 381–392.
Novais, J. S., et al. (2018). Antibacterial naphthoquinone derivatives targeting resistant Gram-negative bacteria in biofilms. Microbial Pathogenesis, 118, 105–114.
Ozturk, I., Tunçel, A., Yurt, F., et al. (2020). Antifungal photodynamic activities of phthalocyanine derivatives on Candida albicans. Photodiagnosis and Photodynamic Therapy, 30, 101688.
Pa, S. T., et al. (2015). Plumbagin induces G2/M arrest, apoptosis, and autophagy via p38 MAPK- and PI3K/Akt/mTOR-mediated pathways in human tongue squamous cell carcinoma cells. Drug Design, Development and Therapy, 9, 1601–1626.
Padhye, S., et al. (2012). Perspectives on medicinal properties of plumbagin and its analogs. Medicinal Research Reviews, 32(6), 1131–1158.
Pereira, A. S. et al. (2018). Metodologia da pesquisa científica. [free ebook]. Santa Maria. Editora da UFSM.
Pereyra, C. E., et al. (2019). The diverse mechanisms and anticancer potential of naphthoquinones. Cancer Cell International, 19, 207.
Perfect, J. R. (2017). The antifungal pipeline: A reality check. Nature Reviews Drug Discovery, 16(9), 603–616.
Perry, N. B., Blunt, J. W., & Munro, M. H. G. (1991). A cytotoxic and antifungal 1,4-naphthoquinone and related compounds from a New Zealand brown alga, Landsburgia quercifolia. Journal of Natural Products, 54(4), 978–985.
Pianalto, K. M., & Alspaugh, J. A. (2016). New horizons in antifungal therapy. Journal of Fungi, 2(4), 26.
Qiu, J. X., et al. (2015). Plumbagin elicits differential proteomic responses in human prostate cancer cells. Drug Design, Development and Therapy, 9, 349–417.
Radwan, M. A., et al. (2017). Oral administration of amphotericin B nanoparticles: Antifungal activity, bioavailability and toxicity in rats. Drug Delivery, 24(1), 40–50.
Rahmoun, N. M., et al. (2012). Antibacterial and antifungal activity of lawsone and novel naphthoquinone derivatives. Médecine et Maladies Infectieuses, 42(6), 270–275.
Ramirez, O., et al. (2014). A small library of synthetic disubstituted 1,4-naphthoquinones induces ROS-mediated cell death. PLoS ONE, 9(9), e106828.
Rauf, A., et al. (2020). Anti-inflammatory, antibacterial, toxicological profile, and in silico studies of dimeric naphthoquinones from Diospyros lotus. BioMed Research International, 2020, 7942549.
Ravelo, Á. G., Estévez-Braun, A., & Pérez-Sacau, E. (2003). The chemistry and biology of lapachol and related natural products. In Studies in Natural Products Chemistry (Vol. 29, pp. 719–760). Elsevier.
Ravichandiran, P., et al. (2019a). 1,4-Naphthoquinone analogues: Potent antibacterial agents and mode of action evaluation. Molecules, 24(7), 1437.
Ravichandiran, P., et al. (2019b). Synthesis and anticancer evaluation of 1,4-naphthoquinone derivatives. ChemMedChem, 14(5), 532–544.
Reshma, R. S., et al. (2016). Plumbagin induces apoptosis in BRCA1/2-defective prostate cancer cells. Pharmacological Research, 105, 134–145.
Revankar, S. G. (2017). Antifúngicos. Manuais MSD – Edição para profissionais. https://www.msdmanuals.com/pt-pt/profissional/doen%C3%A7as-infecciosas/fungos/antif%C3%BAngicos
Richardson, M. D., & Warnock, D. W. (2012). Fungal infection. Wiley-Blackwell.
Rother, E. T. (2007). Revisão sistemática x revisão narrativa. Acta Paulista de Enfermagem. 20(2), 5-6.
Ruther, J., Podsiadlowski, L., & Hilker, M. (2001). Quinones in cockchafers: Additional function of a sex attractant as an antimicrobial agent. Chemoecology, 11(4), 225–229.
Sameni, S., & Hande, M. P. (2016). Plumbagin triggers DNA damage response and genome instability. Biomedicine & Pharmacotherapy, 82, 256–268.
Sánchez-Calvo, J. M., et al. (2016). Synthesis and antibacterial and antifungal activities of naphthoquinone derivatives. Medicinal Chemistry Research, 25(6), 1274–1285.
Sasaki, K., Abe, H., & Yoshizaki, F. (2002). In vitro antifungal activity of naphthoquinone derivatives. Biological and Pharmaceutical Bulletin, 25(5), 669–670.
Satoh, K., et al. (2009). Candida auris sp. nov., a novel ascomycetous yeast. Microbiology and Immunology, 53(1), 41–44.
Shukla, S., et al. (2007). Vitamin K3 and plumbagin are substrates of ABCG2. Molecular Cancer Therapeutics, 6(12), 3279–3286.
Sinawe, H., & Casadeus, D. (2020). Ketoconazole. StatPearls Publishing.
Snyder, H. (2019). Literature review as a research methodology: An overview and guidelines. Journal of Business Research, Elsevier. 104(C), 333-9.
Soares, A. S., et al. (2017). Naphthoquinones of Sinningia reitzii and anti-inflammatory/antinociceptive activities of 8-hydroxydehydrodunnione. Journal of Natural Products, 80(6), 1837–1843.
Sousa, E. T., Lopes, W. A., & Andrade, J. B. (2016). Fontes, formação, reatividade e determinação de quinonas na atmosfera. Química Nova, 39(4), 486–495.
Sousa, N. S. O. et al (2025). Antifungal Activity of Selected Naphthoquinones and Their Synergistic Combination with Amphotericin B Against Cryptococcus neoformans H99. Antibiotics, 14, 602.
Teaford, H. R., et al. (2020). The many faces of itraconazole cardiac toxicity. Mayo Clinic Proceedings: Innovations, Quality & Outcomes.
Tessele, P. B., et al. (2011). A new naphthoquinone isolated from the bulbs of Cipura paludosa and pharmacological activity of two main constituents. Planta Medica, 77(10), 1035–1043.
Tevyashova, A. N., et al. (2020). Discovery of amphamide, a drug candidate for the second generation of polyene antibiotics. ACS Infectious Diseases, 6(8), 2029–2044.
Trisuwan, K., et al. (2010). Anthraquinone, cyclopentanone, and naphthoquinone derivatives from sea fan-derived fungi Fusarium spp. Journal of Natural Products, 73(9), 1507–1511.
Tu, M., et al. (2012). Exploring aromatic chemical space with NEAT: Novel and electronically equivalent aromatic template. Journal of Chemical Information and Modeling, 52(5), 1114–1123.
Vukić, M. D., et al. (2017). Antibacterial and cytotoxic activities of naphthoquinone pigments from Onosma visianii. EXCLI Journal, 16, 73–88.
Wang, F., et al. (2015). Plumbagin induces cell cycle arrest and autophagy and suppresses epithelial-to-mesenchymal transition involving PI3K/Akt/mTOR pathway in human pancreatic cancer cells. Drug Design, Development and Therapy, 9, 537–560.
Wellington, K. W., Nyoka, N. B. P., & McGaw, L. J. (2019). Investigation of the antibacterial and antifungal activity of thiolated naphthoquinones. Drug Development Research, 80(3), 386–394.
Wianowska, D., et al. (2016). Comparison of antifungal activity of extracts from different Juglans regia cultivars and juglone. Microbial Pathogenesis, 100, 263–267.
Yamamoto, Y., et al. (2002). Isofuranonaphthoquinone derivatives from cultures of the lichen Arthonia cinnabarina. Phytochemistry, 60(7), 741–745.
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