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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Coumaric acid analogues inhibit growth and melanin biosynthesis in Cryptococcus neoformans and potentialize amphotericin B antifungal activity

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Author(s):
Oliveira, Lidiane [1] ; Ferrarini, Marcio [2] ; dos Santos, Alexandre Paes [3] ; Varela, Marina Themoteo [2] ; Santos Correa, Isabela Teresa [1] ; Tempone, Andre Gustavo [1] ; Melhem, Marcia S. C. [4, 1] ; Vallim, Marcelo A. [3] ; Fernandes, Joao Paulo S. [2] ; Pascon, Renata C. [3]
Total Authors: 10
Affiliation:
[1] Adolfo Lutz Inst, Ctr Parasitol & Mycol, Ave Dr Arnaldo 355, BR-01246000 Sao Paulo - Brazil
[2] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Rua Sao Nicolau 210, BR-09913030 Diadema, SP - Brazil
[3] Univ Fed Sao Paulo, Biol Sci Dept, Rua Sao Nicolau 210, BR-09913030 Diadema, SP - Brazil
[4] Univ Fed Mato Grosso do Sul, Sch Med, Campo Grande, MS - Brazil
Total Affiliations: 4
Document type: Journal article
Source: European Journal of Pharmaceutical Sciences; v. 153, OCT 1 2020.
Web of Science Citations: 0
Abstract

Fungal infections are on the rise, since the imunocompromised population is increasing due to AIDS/HIV, organ transplant and chemotherapy. Many environmental and pathogenic fungi are able to accomplish melanin biosynthesis as a virulence factor to promote host invasion. Melanized cells are more resistant to radiation, oxidative and osmotic stresses; also melanin confers an advantage in vivo, since melanized cells are more resistant to phagocytic engulfment and oxidative stress caused by the host defense cells and by some antifungal drugs, such as fluconazole (FCZ) and amphotericin B (AmB). Brown, red or black melanin pigments can be produced by the polyketide pathway (DHN-melanin) or from dihydroxyphenols, such as L-DOPA (L-3,4-dihydroxyphenylalanine) and L-tyrosine by polyphenoloxidases. Among several pathogenic fungi, Cryptococcus neoformans is a melanized yeast that causes pneumonia and meningoencephalitis in immunocompromised patients. The knockout of the laccase genes or other interruptions on melanin biosynthetic pathway generates cryptococcal strains with attenuated virulence in an animal model. In this study 16 analogues of coumaric and cinnamic acid were evaluated as possible tyrosinase inhibitors. We have identified some valuable inhibitors of C. neoformans growth and melanin biosynthesis disruption agents. The results showed that coumaric acid derivatives (1a-c), the ketones (3a-b) and 2-allylphenol (7c) are significant inhibitors of tyrosinase and melanization of the fungus. Two analogues (1b and 3b) were selected as promising antimelanogenic agents to be combined with AmB, showing to promote 16-fold reduction in the AmB fungicidal concentration with no appreciable cytotoxicity to mammalian cells. The data suggest that inhibition of the melanin biosynthesis by these compounds may increase the susceptibility of the cells to the oxidative stress generated by AmB. In summary, our data show that C. neoformans can be a suitable model system to test novel inhibitors that target melanin biosynthesis, and novel compounds for adjunct therapy against C. neoformans were identified. (AU)

FAPESP's process: 18/10279-6 - Selection and Optimization of New Drug Candidates for Leishmaniasis and Chagas Disease
Grantee:André Gustavo Tempone Cardoso
Support Opportunities: Regular Research Grants
FAPESP's process: 18/03918-2 - Evaluation of the antiparasitic activity and cytotoxicity of natural products derivatives in Trypanosoma cruzi: design and synthesis of analogues potentially superior
Grantee:Marina Themoteo Varela
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 15/04400-9 - The role of autophagy in Cryptococcus neorformas high temperature (37°C) growth and virulence
Grantee:Marcelo Afonso Vallim
Support Opportunities: Regular Research Grants
FAPESP's process: 16/25028-3 - Antihistamines H3R/H4R as procognitive agents: a multitarget approach
Grantee:João Paulo dos Santos Fernandes
Support Opportunities: Regular Research Grants
FAPESP's process: 16/14542-8 - Genetic characterization of the regulatory elements of the biosynthesis and uptake of amino acids and their role in virulence of Cryptococcus neoformans.
Grantee:Renata Castiglioni Pascon
Support Opportunities: Regular Research Grants