The introduction of antifungals in clinical practice has an enormous impact on the provision of medical care, increasing the expectancy and quality of life mainly of immunocompromised patients. However, the emergence of pathogenic fungi that are resistant and multi-resistant to the existing antifungal therapy has culminated in fungal infections that are almost impossible to treat. Therefore, there is an urgent need to discover new strategies. The marine environment has proven to be a promising rich resource for the discovery and development of new antifungal compounds. Thus, this review summarizes more than one hundred marine natural products, or their derivatives, which are categorized according to their sources—sponges, bacteria, fungi, and sea cucumbers—as potential candidates as antifungal agents. In addition, this review focus on recent developments using marine antifungal compounds as new and effective approaches for the treatment of infections caused by resistant and multi-resistant pathogenic fungi and/or biofilm formation; other perspectives on antifungal marine products highlight new mechanisms of action, the combination of antifungal and non-antifungal agents, and the use of nanoparticles and anti-virulence therapy.

Marine biofouling is a natural process that represents major economic, environmental, and health concerns. Some booster biocides have been used in biofouling control, however, they were found to accumulate in environmental compartments, showing negative effects on marine organisms. Therefore, it is urgent to develop new eco-friendly alternatives. Phenyl ketones, such as benzophenones and acetophenones, have been described as modulators of several biological activities, including antifouling activity (AF). In this work, acetophenones were combined with other chemical substrates through a 1,2,3-triazole ring, a strategy commonly used in Medicinal Chemistry. In our approach, a library of 14 new acetophenone–triazole hybrids was obtained through the copper(I)-catalyzed alkyne-azide cycloaddition “click” reaction. All of the synthesized compounds were evaluated against the settlement of a representative macrofouling species, Mytilus galloprovincialis, as well as on biofilm-forming marine microorganisms, including bacteria and fungi. The growth of the microalgae Navicula sp. was also evaluated after exposure to the most promising compounds. While compounds 6a, 7a, and 9a caused significant inhibition of the settlement of mussel larvae, compounds 3b, 4b, and 7b were able to inhibit Roseobacter litoralis bacterial biofilm growth. Interestingly, acetophenone 7a displayed activity against both mussel larvae and the microalgae Navicula sp., suggesting a complementary action of this compound against macro- and microfouling species. The most potent compounds (6a, 7a, and 9a) also showed to be less toxic to the non-target species Artemia salina than the biocide Econea^®. Regarding both AF potency and ecotoxicity activity evaluation, acetophenones 7a and 9a were put forward in this work as promising eco-friendly AF agents.

Fungal infections are one of the main causes of mortality and morbidity worldwide and taking into account the increasing incidence of strains resistant to classical antifungal drugs, the development of new agents has become an urgent clinical need. Considering that thioxanthones are bioisosteres of xanthones with known anti-infective actions, their scaffolds were selected for this study. A small library of synthesized aminothioxanthones (1–10) was evaluated for in vitro antifungal activity against Candida albicans, Aspergillus fumigatus, and Trichophyton rubrum; for the active compounds, the spectrum was further extended to other clinically relevant pathogenic fungi. The results showed that only compounds 1, 8, and 9 exhibited inhibitory and broad-spectrum antifungal effects. Given the greater antifungal potential presented, compound 1 was the subject of further investigations to study its anti-virulence activity and in an attempt to elucidate its mechanism of action; compound 1 seems to act predominantly on the cellular membrane of C. albicans ATCC 10231, altering its structural integrity, without binding to ergosterol, while inhibiting two important virulence factors—dimorphic transition and biofilm formation—frequently associated with C. albicans pathogenicity and resistance. In conclusion, the present work proved the usefulness of thioxanthones in antifungal therapy as new models for antifungal agents.

Systemic fungal infections caused by filamentous fungi, particularly in the immunocompromised population, represent a serious threat to public health. The increase in resistant strains to classic antifungal drugs, especially azoles, is a global health problem, with some infections becoming almost impossible to treat. Furthermore, the emergence of new multidrug-resistant fungal species, such as Scedosporium spp. and Fusarium spp., as etiological agents, poses a challenge in treatment. On the other hand, superficial fungal infections caused by dermatophytes have a high incidence rate, affecting approximately 20 to 30% of the healthy human population. Therefore, the discovery and development of new broad-spectrum antifungal compounds able to modulate and/or eradicate antifungal resistance have become an essential and urgent task. Taking into account that thioxanthones are privileged structures and bioisosteres of xanthones, three thioxanthones were synthesized and, subsequently, their activity as potential agents against filamentous fungi was evaluated. A minimum inhibitory concentration and minimum lethal concentration was tested against clinically relevant species using the broth microdilution method. The derivatives were synthesized through aromatic nucleophilic substitution reactions using a chlorinated thioxanthone and a primary amine as the building blocks. This showed interesting results against most of the isolates tested, including intrinsically resistant strains or those that acquired resistance to fluconazole or other azoles; among the tested compounds, one of the thioxanthone showed more promising activity. These findings highlight the potential value of thioxanthone derivatives as new models for antifungal agents for the treatment of systemic and superficial fungal infections.