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Fungal infections are a significant threat to human health and the environment. The emergence of multidrug-resistant strains of fungi and the growing prevalence of azole resistance in invasive fungal infections exacerbate the problem, with efflux pumps being a major cause of antifungal resistance and a prime target for several counteractive strategies. In Candida albicans, the ATP-binding cassette superfamily transporter CaCdr1p is the predominant efflux pump involved in azole resistance. Marine organisms have unique phenotypic characteristics to survive in challenging environments, resulting in biologically active compounds. The cyclodepsipeptides unnarmicin A and C have shown promising results as inhibitors of rhodamine 6G efflux in cells expressing CaCdr1p. Herein, a series of unnarmicin analogues were designed and docked against a CaCdr1p efflux pump based on the cryogenic electron microscopy structure available to select the most promising compounds. Analogue 33 was predicted to be the best considering its high affinity for the efflux pump and pharmacokinetic profile. These results pave the way for further synthesis and in vitro biological studies of novel unnarmicins seeking a synergistic effect with fluconazole.

The pursuit of cosmetic ingredients with proven efficacy and safety that meet consumer needs drives the advancement of new products. Ascorbic acid (AA) is utilized in cosmetic products, predominantly for its potent antioxidant properties. Nonetheless, its instability compromises its efficacy. In this work, ascorbyl 2-O-glucoside persulfate (AAGS) was synthesized, characterized, and evaluated regarding its safety profile and potential bioactivities and the results were compared to AA and its glycoside AAG. Pre-formulation studies were performed to assess the stability of the compounds and their compatibility with typical excipients commonly used in topical formulations. AAGS did not affect the metabolic activity of keratinocyte, macrophage, and monocyte cell lines, up to 500 µM. AAGS also exhibited a non-prooxidant and non-sensitizing profile and anti-allergic activity by impeding the allergen-induced maturation of THP-1 cells. When compared to AA and AAG, AAGS was shown to be more stable at pH values between 5 and 7, as well as superior thermostability and photostability. AAGS demonstrated higher stability in metal solutions of Fe(II) and Mg(II) than AA. AAGS demonstrated similar DPPH radical scavenging activity compared to AA. These results provide useful information for the development of new AA derivatives, highlighting AAGS as a novel cosmetic ingredient.

The current scenario of antifouling (AF) strategies to prevent the natural process of marine biofouling is based in the use of antifouling paints containing different active ingredients, believed to be harmful to the marine environment. Compounds called booster biocides are being used with copper as an alternative to the traditionally used tributyltin (TBT); however, some of them were recently found to accumulate in coastal waters at levels that are deleterious for marine organisms. More ecological alternatives were pursued, some of them based on the marine organism mechanisms’ production of specialized metabolites with AF activity. However, despite the investment in research on AF natural products and their synthetic analogues, many studies showed that natural AF alternatives do not perform as well as the traditional metal-based ones. In the search for AF agents with better performance and to understand which molecular motifs were responsible for the AF activity of natural compounds, synthetic analogues were produced and investigated for structure–AF activity relationship studies. This review is a comprehensive compilation of AF compounds synthesized in the last two decades with highlights on the data concerning their structure–activity relationship, providing a chemical toolbox for researchers to develop efficient nature-inspired AF agents.

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Global health faces a significant issue with the rise of infectious diseases caused by bacteria, fungi, viruses, and parasites. The increasing number of multi-drug resistant microbial pathogens severely threatens public health worldwide. Antibiotic-resistant pathogenic bacteria, in particular, present a significant challenge. Therefore, there is an urgent need to identify new potential antimicrobial targets and discover new chemical entities that can potentially reverse bacterial resistance. The main goal of this research work was to create and develop a library of 3,6-disubstituted xanthones based on twin drugs and molecular extension approaches to inhibit the activity of efflux pumps. The process involved synthesizing 3,6-diaminoxanthones through the reaction of 9-oxo-9H-xanthene-3,6-diyl bis(trifluoromethanesulfonate) with various primary and secondary amines. The resulting 3,6-disubstituted xanthone derivatives were then tested for their in vitro antimicrobial properties against a range of pathogenic strains and their efficacy in inhibiting the activity of efflux pumps, biofilm formation, and quorum-sensing. Several compounds have exhibited effective antibacterial properties against the Gram-positive bacterial species tested. Xanthone 16, in particular, has demonstrated exceptional efficacy with a remarkable MIC of 11 µM (4 µg/mL) against reference strains Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212, and 25 µM (9 µg/mL) against methicillin-resistant S. aureus 272123. Furthermore, some derivatives have shown potential as antibiofilm agents in a crystal violet assay. The ethidium bromide accumulation assay pinpointed certain compounds inhibiting bacterial efflux pumps. The cytotoxic effect of the most promising compounds was examined in mouse fibroblast cell line NIH/3T3, and two monoamine substituted xanthone derivatives with a hydroxyl substituent did not exhibit any cytotoxicity. Overall, the nature of the substituent was critical in determining the antimicrobial spectra of aminated xanthones.

Glioblastoma (GBM) is the most common and deadly primary malignant brain tumor. Current therapies are insufficient, and survival for individuals diagnosed with GBM is limited to a few months. New GBM treatments are urgent. Polymeric nanoparticles (PNs) can increase the circulation time of a drug in the brain capillaries. Polymersomes (PMs) are PNs that have been described as having attractive characteristics, mainly due to their stability, prolonged circulation period, biodegradability, their ability to sustain the release of drugs, and the possibility of surface functionalization. In this work, a poly(ethylene glycol)-ε-caprolactone (PEG-PCL) copolymer was synthesized and PMs were prepared and loaded with an hydrolytic instable compound, previously synthesized by our research team, the 3,6-bis(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl)xanthone (XGAc), with promising cytotoxicity on glioblastoma cells (U-373 MG) but also on healthy cerebral endothelial cells (hCMEC/D3). The prepared PMs were spherical particles with uniform morphology and similar sizes (mean diameter of 200 nm) and were stable in aqueous suspension. The encapsulation of XGAc in PMs (80% encapsulation efficacy) protected the healthy endothelial cells from the cytotoxic effects of this compound, while maintaining cytotoxicity for the glioblastoma cell line U-373 MG. Our studies also showed that the prepared PMs can efficiently release XGAc at intratumoral pHs.

Depigmenting products are increasingly used to counteract skin hyperpigmentation and related psychosocial issues. This study aimed to compare different depigmenting agents—4-butylresorcinol; bakuchiol; tranexamic acid; ascorbyl glucoside; α-arbutin; and ascorbic acid—for photoreactivity; tyrosinase inhibition; and safety. Photoreactivity was assessed using the Reactive Oxygen Species assay. In vitro tyrosinase inhibition was compared, and cell viability was assessed in B-16V melanocytes to evaluate safety. Results showed 4-butylresorcinol, ascorbyl glucoside, and α-arbutin are non-photoreactive, while for ascorbic acid and bakuchiol it was not possible to reach conclusive results due to the lack of specificity of the ROS assay. 4-Butylresorcinol, acting as a competitive inhibitor, displayed potent tyrosinase inhibition, followed by ascorbic acid and bakuchiol. Both 4-butylresorcinol and bakuchiol reduced cell viability in a concentration-dependent manner. The insights obtained in this work support the development of depigmenting products by providing useful scientific guidance on the photostability, tyrosinase inhibitory efficacy, and skin safety of depigmenting agents.

Parasitic diseases still compromise human health. Some of the currently available therapeutic drugs have limitations considering their adverse effects, questionable efficacy, and long treatment, which have encouraged drug resistance. There is an urgent need to find new, safe, effective, and affordable antiparasitic drugs. Marine-derived cyclic peptides have been increasingly screened as candidates for developing new drugs. Therefore, in this review, a systematic analysis of the scientific literature was performed and 25 marine-derived cyclic peptides with antiparasitic activity (1–25) were found. Antimalarial activity is the most reported (51%), followed by antileishmanial (27%) and antitrypanosomal (20%) activities. Some compounds showed promising antiparasitic activity at the nM scale, being active against various parasites. The mechanisms of action and targets for some of the compounds have been investigated, revealing different strategies against parasites.

Natural products are a very rich source for obtaining new compounds with therapeutic potential. In the search for new antiparasitic and antimicrobial agents, molecular hybrids were designed based on the structures of antimicrobial marine quinazolinones and eugenol, a natural phenolic compound. Following reports of the therapeutic potential of quinazolinones and eugenol derivatives, it was expected that the union of these pharmacophores could generate biologically relevant substances. The designed compounds were obtained by classical synthetic procedures and were characterized by routine spectrometric techniques. Nine intermediates and final products were then evaluated in vitro against Trypanosoma brucei and Leishmania infantum. Antifungal and antibacterial activity were also evaluated. Six compounds (9b, 9c, 9d, 10b, 10c, and 14) showed mild activity against T. brucei with IC50 in the range of 11.17–31.68 μM. Additionally, intermediate 9c showed anti-Leishmania activity (IC50 7.54 μM) and was six times less cytotoxic against THP-1 cells. In conclusion, novel derivatives with a simple quinazolinone scaffold showing selectivity against parasites without antibacterial and antifungal activities were disclosed, paving the way for new antitrypanosomal agents.

The spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) relies on host cell surface glycans to facilitate interaction with the angiotensin-converting enzyme 2 (ACE-2) receptor. This interaction between ACE2 and the spike protein is a gateway for the virus to enter host cells and may be targeted by antiviral drugs to inhibit viral infection. Therefore, targeting the interaction between these two proteins is an interesting strategy to prevent SARS-CoV-2 infection. A library of glycan mimetics and derivatives was selected for a virtual screening performed against both ACE2 and spike proteins. Subsequently, in vitro assays were performed on eleven of the most promising in silico compounds to evaluate: (i) their efficacy in inhibiting cell infection by SARS-CoV-2 (using the Vero CCL-81 cell line as a model), (ii) their impact on ACE2 expression (in the Vero CCL-81 and MDA-MB-231 cell lines), and (iii) their cytotoxicity in a human lung cell line (A549). We identified five synthetic compounds with the potential to block SARS-CoV-2 infection, three of them without relevant toxicity in human lung cells. Xanthene 1 stood out as the most promising anti-SARS-CoV-2 agent, inhibiting viral infection and viral replication in Vero CCL-81 cells, without causing cytotoxicity to human lung cells.

Marine natural products are well-recognized as potential resources to fill the pipeline of drug leads to enter the pharmaceutical industry. In this circumstance, marine-derived fungi are one of the unique sources of bioactive secondary metabolites due to their capacity to produce diverse polyketides and peptides with unique structures and diverse biological activities. The present review covers the peptides from marine-derived fungi reported from the literature published from January 1991 to June 2023, and various scientific databases, including Elsevier, ACS publications, Taylor and Francis, Wiley Online Library, MDPI, Springer, Thieme, Bentham, ProQuest, and the Marine Pharmacology website, are used for a literature search. This review focuses on chemical characteristics, sources, and biological and pharmacological activities of 366 marine fungal peptides belonging to various classes, such as linear, cyclic, and depsipeptides. Among 30 marine-derived fungal genera, isolated from marine macro-organisms such as marine algae, sponges, coral, and mangrove plants, as well as deep sea sediments, species of Aspergillus were found to produce the highest number of peptides (174 peptides), followed by Penicillium (23 peptides), Acremonium (22 peptides), Eurotium (18 peptides), Trichoderma (18 peptides), Simplicillium (17 peptides), and Beauveria (12 peptides). The cytotoxic activity against a broad spectrum of human cancer cell lines was the predominant biological activity of the reported marine peptides (32%), whereas antibacterial, antifungal, antiviral, anti-inflammatory, and various enzyme inhibition activities ranged from 7% to 20%. In the first part of this review, the chemistry of marine peptides is discussed and followed by their biological activity.

Cyclic peptides are molecules that are already used as drugs in therapies approved for various pharmacological activities, for example, as antibiotics, antifungals, anticancer, and immunosuppressants. Interest in these molecules has been growing due to the improved pharmacokinetic and pharmacodynamic properties of the cyclic structure over linear peptides and by the evolution of chemical synthesis, computational, and in vitro methods. To date, 53 cyclic peptides have been approved by different regulatory authorities, and many others are in clinical trials for a wide diversity of conditions. In this review, the potential of cyclic peptides is presented, and general aspects of their synthesis and development are discussed. Furthermore, an overview of already approved cyclic peptides is also given, and the cyclic peptides in clinical trials are summarized.

Five undescribed pentaketide derivatives, (R)-6,8-dihydroxy-4,5-dimethyl-3-methylidene-3,4-dihydro-1H-2-benzopyran-1-one (1), [(3S,4R)-3,8-dihydroxy-6-methoxy-4,5-dimethyl-1-oxo-3,4-dihydro-1H-isochromen-3-yl]methyl acetate (2), (R)-5, 7-dimethoxy-3-((S)-(1-hydroxyethyl)-3,4-dimethylisobenzofuran-1(3H)-one (4b), (S)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran 1(3H)-one (5), and a p-hydroxyphenyl-2-pyridone derivative, avellaneanone (6), were isolated together with the previously reported (R)-3-acetyl-7-hydroxy-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (3), (R)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (4a) and isosclerone (7), from the ethyl acetate extract of a culture of a marine sponge-derived fungus, Hamigera avellanea KUFA0732. The structures of the undescribed compounds were elucidated using 1D and 2D NMR, as well as high-resolution mass spectral analyses. The absolute configurations of the stereogenic carbons in 1, 4b, 5, and 6 were established by X-ray crystallographic analysis. The absolute configurations of C-3 and C-4 in 2 were determined by ROESY correlations and on the basis of their common biosynthetic origin with 1. The crude fungal extract and the isolated compounds 1, 3, 4b, 5, 6, and 7 were assayed for their growth inhibitory activity against various plant pathogenic fungi viz. Alternaria brassicicola, Bipolaris oryzae, Colletotrichum capsici, C. gloeosporiodes, Curvularia oryzae, Fusarium semitectum, Lasiodiplodia theobromae, Phytophthora palmivora, Pyricularia oryzae, Rhizoctonia oryzae and Sclerotium rolfsii.

Drug resistance is rising to alarming levels, constituting one of the major threats to global health. The overexpression of efflux pumps and the formation of biofilms constitute two of the most common resistance mechanisms, favoring the virulence of bacteria. Therefore, the research and development of effective antimicrobial agents that can also counteract resistance mechanisms are extremely important. Pyrazino[2,1-b]quinazoline-3,6-diones, from marine and terrestrial organisms and simpler synthetic analogues, were recently disclosed by us as having relevant antimicrobial properties. In this study, using a multi-step approach, it was possible to synthesize new pyrazino[2,1-b]quinazoline-3,6-diones focusing on compounds with fluorine substituents since, to the best of our knowledge, the synthesis of fluorinated fumiquinazoline derivatives had not been attempted before. The new synthesized derivatives were screened for antibacterial activity and, along with previously synthetized pyrazino[2,1-b]quinazoline-3,6-diones, were characterized for their antibiofilm and efflux-pump-inhibiting effects against representative bacterial species and relevant resistant clinical strains. Several compounds showed relevant antibacterial activity against the tested Gram-positive bacterial species with MIC values in the range of 12.5–77 μM. Furthermore, some derivatives showed promising results as antibiofilm agents in a crystal violet assay. The results of the ethidium bromide accumulation assay suggested that some compounds could potentially inhibit bacterial efflux pumps.

Skin repair encompasses epidermal barrier repair and wound healing which involves multiple cellular and molecular stages. Therefore, many skin repair strategies have been proposed. In order to characterize the usage frequency of skin repair ingredients in cosmetics, medicines, and medical devices, commercialized in Portuguese pharmacies and parapharmacies, a comprehensive analysis of the products’ composition was performed. A total of 120 cosmetic products, collected from national pharmacies online platforms, 21 topical medicines, and 46 medical devices, collected from INFARMED database, were included in the study, revealing the top 10 most used skin repair ingredients in these categories. A critical review regarding the effectiveness of the top ingredients was performed and an in-depth analysis focused on the top three skin repair ingredients pursued. Results demonstrated that top three most used cosmetic ingredients were metal salts and oxides (78.3%), vitamin E and its derivatives (54.2%), and Centella asiatica (L.) Urb. extract and actives (35.8%). Regarding medicines, metal salts and oxides were also the most used (47.4%) followed by vitamin B5 and derivatives (23.8%), and vitamin A and derivatives (26.3%). Silicones and derivatives were the most common skin repair ingredients in medical devices (33%), followed by petrolatum and derivatives (22%) and alginate (15%). This work provides an overview of the most used skin repair ingredients, highlighting their different mechanisms of action, aiming to provide an up-to-date tool to support health professionals’ decisions.

Resveratrol (RSV), a naturally occurring metabolite, is widely used in skincare products, but its hydrophobicity impairs its own incorporation into cosmetic formulations. RSV-GS is a synthetic hydrophilic sulfated glycosylated derivative inspired by marine natural products that present a lower cytotoxicity than RSV while exhibiting similar levels of bioactivity. Herein, we predict the skin sensitization potential of this new compound using an in vitro approach based on the OECD 442E guideline. Furthermore, the anti-allergic potential of RSV-GS was also disclosed. The monocyte THP-1 cell line was stimulated with RSV and RSV-GS in the presence or absence of the extreme skin allergen 1-fluoro-2,4-dinitrobenzene (DNFB). The results demonstrated that RSV-GS alone (500 µM) evoked a relative fluorescence index (RFI) lower than the thresholds established by the OECD guideline for CD54 (200%) and CD86 (150%), indicating the absence of a skin sensitization potential. Interestingly, in the presence of the skin allergen DNFB, RSV-GS exhibited the ability to rescue the DNFB-induced maturation of THP-1 cells, with RFI values lower than those for RSV, suggesting the potential of RSV-GS to mitigate skin sensitization evoked by allergens and, consequently, allergic contact dermatitis. These results open new avenues for the use of RSV-GS as a safe and anti-allergic active cosmetic ingredient.

An undescribed hybrid phenalenone dimer, talaropinophilone (3), an unreported azaphilone, 7-epi-pinazaphilone B (4), an unreported phthalide dimer, talaropinophilide (6), and an undescribed 9R,15S-dihydroxy-ergosta-4,6,8 (14)-tetraen-3-one (7) were isolated together with the previously reported bacillisporins A (1) and B (2), an azaphilone derivative, Sch 1385568 (5), 1-deoxyrubralactone (8), acetylquestinol (9), piniterpenoid D (10) and 3,5-dihydroxy-4-methylphthalaldehydic acid (11) from the ethyl acetate extract of the culture of a marine sponge-derived fungus, Talaromyces pinophilus KUFA 1767. The structures of the undescribed compounds were elucidated by 1D and 2D NMR as well as high-resolution mass spectral analyses. The absolute configuration of C-9′ of 1 and 2 was revised to be 9′S using the coupling constant value between C-8′ and C-9′ and was confirmed by ROESY correlations in the case of 2. The absolute configurations of the stereogenic carbons in 7 and 8 were established by X-ray crystallographic analysis. Compounds 1,2, 4–8, 10 and 11 were tested for antibacterial activity against four reference strains, viz. two Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and two Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), as well as three multidrug-resistant strains, viz. an extended-spectrum β-lactamase (ESBL)-producing E. coli, a methicillin-resistant S. aureus (MRSA) and a vancomycin-resistant E. faecalis (VRE). However, only 1 and 2 exhibited significant antibacterial activity against both S. aureus ATCC 29213 and MRSA. Moreover, 1 and 2 also significantly inhibited biofilm formation in S. aureus ATCC 29213 at both MIC and 2xMIC concentrations.

Ultraviolet (UV) radiation promotes the generation of reactive oxygen species (ROS) and nitrogen species (RNS), resulting in skin damage. Cosmetic industries have adopted a strategy to incorporate antioxidants in sunscreen formulations to prevent or minimize UV-induced oxidative damage, boost photoprotection effectiveness, and mitigate skin photoaging. Many antioxidants are naturally derived, mainly from terrestrial plants; however, marine organisms have been increasingly explored as a source of new potent antioxidant molecules. This work aims to characterize the frequency of the use of antioxidants in commercial sunscreens. Photoprotective formulations currently marketed in parapharmacies and pharmacies were analyzed with respect to the composition described on the label. As a result, pure compounds with antioxidant activity were found. The majority of sunscreen formulations contained antioxidants, with vitamin E and its derivatives the most frequent. A more thorough analysis of these antioxidants is also provided, unveiling the top antioxidant ingredients found in sunscreens. A critical appraisal of the scientific evidence regarding their effectiveness is also performed. In conclusion, this work provides an up-to-date overview of the use of antioxidants in commercial sunscreens for a better understanding of the advantages associated with their use in photoprotective formulations.

The virtual screening of a library of chalcone derivatives led us to the identification of potential new MDM2 ligands. The chalcones with the best docking scores obeying the Lipinski rule of five were subsequently prepared by base-catalyzed aldol reactions. The activity of these compounds as inhibitors of p53–MDM2 interaction was investigated using a yeast-based screening assay. Using this approach two chalcones (3 and 4) were identified as putative small molecule inhibitors of p53–MDM2 interaction. The activity of both chalcones was further investigated in a panel of human tumor cells. Chalcones 3 and 4 revealed a pronounced tumor cell growth inhibitory effect on tumor cell lines. Additionally, chalcone 4 caused alterations in the cell cycle profile, induced apoptosis and increased the levels of p53, p21 and PUMA proteins in NCI-H460 cells. Computational docking studies allowed to predict that, like nutlin-3A (a well-known small-molecule inhibitor of p53–MDM2 interaction), chalcones 3 and 4 bind to the p53-binding site of MDM2. The results here presented will be valuable for the structure-based design of novel and potent p53–MDM2 inhibitors. Keywords: Chalcones, p53–MDM2 interaction inhibitors, In vitro antitumor activity, Docking

The accumulation of marine biofouling on ship hulls causes material damage, the spread of invasive species, and, indirectly, an increase in full consumption and subsequent pollutant gas emissions. Most efficient antifouling (AF) strategies rely on the conventional release of persistent, bioaccumulative, and toxic biocides incorporated in marine coatings. A simple oxygenated xanthone, 3,4-dihydroxyxanthone (1), was previously reported as a promising AF agent toward the settlement of Mytilus galloprovincialis larvae, with a therapeutic ratio higher than the commercial biocide Econea®. In this work, a structure-AF activity relationship study, an evaluation of environmental fate, and an AF efficiency in marine coatings were performed with compound 1. Hydroxy or methoxy groups at 3 and 4 positions in compound 1 favored AF activity, and groups with higher steric hindrances were detrimental. Compound 1 demonstrated low water-solubility and a short half-life in natural seawater, contrary to Econea®. In silico environmental fate predictions showed that compound 1 does not bioaccumulate in organism tissues, in contrast to other current emerging biocides, has a moderate affinity for sediments and slow migrates to ground water. No toxicity was observed against Vibrio fischeri and Phaeodactylum tricornutum. Polyurethane-based marine coatings containing compound 1 prepared through an innovative non-release-strategy were as efficient as those containing Econea® with low releases to water after 45 days. This proof-of-concept helped to establish compound 1 as a promising eco-friendly AF agent.

With antimicrobial resistance reaching critical levels worldwide, the development of new compounds that are effective against resistant bacterial pathogens or that can potentiate the effect of known antibiotics is an urgent need. The formation of biofilms and the overexpression of efflux pumps are some of the most common causes of drug resistance. Previous work from our group has shown that alkaloids related to the fumiquinazolines have antibacterial potential. Herein we aimed to synthesize a small library of fumiquinazoline-related alkaloids and to study their antibacterial and anti-biofilm activities as well as their capacity to inhibit bacterial efflux pumps. To achieve these goals, two naturally occurring alkaloids, as well as several new derivatives, were synthesized through a multi-step synthetic pathway. The screening of their antibacterial activities was achieved by determination of the minimum inhibitory concentration of each compound against a panel of clinically relevant bacterial species. Several compounds exhibited promising activities against Gram-positive bacteria. Then, using the ethidium bromide accumulation assay, it was possible to identify some compounds with capacity to inhibit efflux pumps. Some of the synthesized alkaloids also showed anti-biofilm potential, reinforcing the idea that fumiquinazoline-related alkaloids can constitute a key strategy for fighting antimicrobial resistance.

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.

The effective response of antibiotics is threatened by the proliferation of micro-organisms that manifest resistance mechanisms, leading to an increase of progressively untreatable infectious diseases around the world. One solution to this problem could lie in shifting the strategy from searching for new antibacterials to discovering new compounds that potentiate the antimicrobial activity of current antibiotics, therefore reverting resistance, through the interference with several mechanisms including biofilm formation and efflux pumps (EPs). Using bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) as a template, a macroalgae brominated bromophenol with antimicrobial activity, a series of 18 chalcone derivatives was prepared and evaluated for its antimicrobial activity and potential to fight antibiotic resistance. This includes seven chalcones, six dihydrochalcones and five diarylpropanes. Among them, two chalcones exhibited interesting antifungal activity and all compounds reversed resistance to vancomycin in the environmental isolate Enterococcus faecalis B3/101. Three compounds caused a four-fold decrease in the minimum inhibitory concentration (MIC) values of vancomycin against E. faecalis. All the dihydrochalcones and diarylpropanes displayed inhibition of EPs and biofilm formation in the tested multidrug-resistant strain, suggesting that these compounds are EP inhibitors. Notably, dihydrochalcones and diarylpropanes did not show cytotoxicity in a mouse embryonic fibroblast cell line and they can potentially be regarded as hits for bacterial EP inhibition.

The 1,2,3-triazole ring has been gaining increased attention in medicinal chemistry over the past few years since it has been associated with metabolic stability and several biological activities, including antifouling. Therefore, the hybridization of this heterocycle with other pharmacophores which showed ability to prevent marine biofouling can be a strategy to obtain more effective and stable compounds. Marine biofouling remains a huge challenge for maritime industries and public health, causing economic, human, and ecological concerns, with few environmentally safe options to prevent this phenomenon. Considering that the incorporation of an acetophenone into coatings was found to decrease the attachment of marine micro- and macro-organisms, and in an attempt to obtain new effective acetophenone derivatives, a series of triazolyl acetophenones were obtained, through hybridization with the 1,2,3-triazole ring and other pharmacophores, using the copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) methodology. Fourteen new acetophenone-1,2,3-triazole hybrids were obtained and screening against the settlement of the macrofouling mussel Mytilus galloprovincialis and on five biofilm-forming marine bacteria allowed identifying promising compounds. Three compounds were able to inhibit the growth of marine bacteria Roseobacter litoralis, while the other three compounds significantly inhibited the settlement of mussel larvae. For those, the ability to inhibit the growth of Navicula sp. microalgae was also evaluated. One acetophenone was found to display complementary antifouling activity against macrofouling mussel and microalgae Navicula sp. The most potent compounds also were shown to be less toxic to the non-target species Artemia salina than the commercial biocide Econea®.

UV filters are the shield ingredients of sunscreens against the negative effects of solar radiation. Since the discovery of the first UV filter, nearly 30 filters have become commercially available. Over the years, innovation and regulatory updates have driven their use by the cosmetic industry. This work aimed to characterize commercial sunscreens and unveil the main trends by analyzing the labels of 444 sunscreen formulations that are currently being marketed. Avobenzone, octocrylene, and bis-ethylhexyloxyphenol methoxyphenyl triazine were the three UV filters with the highest usage frequencies (>40%). Emulsified preparations and sprays were the preferred forms, while the most frequent SPF was 50+. Differences were noted between adult and children’s sunscreens, namely the higher usage of inorganic filters for the latter. Over the past few years, the five most used UV filters remained the same, but octocrylene, ethylhexyl salicylate, and nano methylene bis-benzotriazolyl tetramethylbutylphenol had decreased usage. An increasing tendency towards the use of the inorganic UV filter titanium oxide was also observed. Overall, this study characterized the true market impact of approved UV filters and how the market has evolved over recent years. This insight can help pave the way for the design of new UV filters and is helpful for the assessment of environmental risks.

Resistance to antibiotics is an emerging problem worldwide, which leads to an increase in morbidity and mortality rates. Several mechanisms are attributed to bacterial resistance, overexpression of efflux pumps being one of the most prominent. As an attempt to develop new effective antimicrobial drugs, which could be able to act against resistant bacterial strains and considering the antimicrobial potential of flavonoids and triazolyl flavonoid derivatives, in particular chalcones, a small library of chalcone derivatives was synthesized and evaluated for its potential to act as antimicrobials and/or adjuvants in combination with antibiotics towards resistant bacteria. Although only compound 7 was able to act as antibacterial, compounds 1, 2, 4, 5, 7, and 9 revealed to be able to potentiate the activity of antibiotics in resistant bacteria. Moreover, five compounds (3, 5–8) demonstrated to be effective inhibitors of efflux pumps in Salmonella enterica serovar Typhimurium SL1344, and four compounds (1, 3, 7, and 10) showed higher ability than reserpine to inhibit biofilm formation of resistant Staphylococcus aureus 272123. Together, our results showed the potential of these compounds regarding reversion of bacterial resistance.

The overexpression of efflux pumps is one of the strategies used by bacteria to resist antibiotics and could be targeted to circumvent the antibiotic crisis. In this work, a series of trimethoxybenzoic acid derivatives previously described as antifouling compounds was explored for potential antimicrobial activity and efflux pump (EP) inhibition. First, docking studies on the acridine resistance proteins A and B coupled to the outer membrane channel TolC (AcrAB-TolC) efflux system and a homology model of the quinolone resistance protein NorA EP were performed on 11 potential bioactive trimethoxybenzoic acid and gallic acid derivatives. The synthesis of one new trimethoxybenzoic acid derivative (derivative 13) was accomplished. To investigate the potential of this series of 11 derivatives as antimicrobial agents, and in reverting drug resistance, the minimum inhibitory concentration was determined on several strains (bacteria and fungi), and synergy with antibiotics and EP inhibition were investigated. Derivative 10 showed antibacterial activity against the studied strains, derivatives 5 and 6 showed the ability to inhibit EPs in the acrA gene inactivated mutant Salmonella enterica serovar Typhimurium SL1344, and 6 also inhibited EPs in Staphylococcus aureus 272123. Structure-activity relationships highlighted trimethoxybenzoic acid as important for EP inhibitory activity. Although further studies are necessary, these results show the potential of simple trimethoxybenzoic acid derivatives as a source of feasible EP inhibitors.

Fungal conditions affect a multitude of people worldwide, leading to increased hospitalization and mortality rates, and the need for novel antifungals is emerging with the rise of resistance and immunocompromised patients. Continuous use of azole drugs, which act by inhibiting the fungal CYP51, involved in the synthesis of ergosterol, essential to the fungal cell membrane, has enhanced the resistance and tolerance of some fungal strains to treatment, thereby limiting the arsenal of available drugs. The goal of this review is to gather literature information on new promising azole developments in clinical trials, with in vitro and in vivo results against fungal strains, and complementary assays, such as toxicity, susceptibility assays, docking studies, among others. Several molecules are reviewed as novel azole structures in clinical trials and with recent/imminent approvals, as well as other innovative molecules with promising antifungal activity. Structure–activity relationship (SAR) studies are displayed whenever possible. The azole moiety is brought over as a privileged structure, with multiple different compounds emerging with distinct pharmacophores and SAR. Particularly, 1,2,3-triazole natural product conjugates emerged in the last years, presenting promising antifungal activity and a broad spectrum against various fungi.

Natural products have attracted attention due to their safety and potential effectiveness as anti-inflammatory drugs. Particularly, xanthones owning a unique 9H-xanthen-9-one scaffold, are endowed with a large diversity of medical applications, including antioxidant and anti-inflammatory activities, because their core accommodates a vast variety of substituents at different positions. Among others, α- and γ-mangostin are the major known xanthones purified from Garcinia mangostana with demonstrated anti-inflammatory and antioxidant effects by in vitro and in vivo modulation of the Nrf2 (nuclear factor erythroid-derived 2-like 2) pathway. However, the main mechanism of action of xanthones and their derivatives is still only partially disclosed, and further investigations are needed to improve their potential clinical outcomes. In this light, a library of xanthone derivatives was synthesized and biologically evaluated in vitro on human macrophages under pro-inflammatory conditions. Furthermore, structure–activity relationship (SAR) studies were performed by means of matched molecular pairs (MMPs). The data obtained revealed that the most promising compounds in terms of biocompatibility and counteraction of cytotoxicity are the ones that enhance the Nrf2 translocation, confirming a tight relationship between the xanthone scaffold and the Nrf2 activation as a sign of intracellular cell response towards oxidative stress and inflammation.

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.

Once more under the auspices of the Sociedade Portuguesa de Química, two important fields of Chemistry are brought together into a single event, the 14th National Organic Chemistry Meeting and the 7th National Medicinal Chemistry Meeting. These conferences brought together both long-recognized experts and newcomers.

The development of marine-inspired compounds as non-toxic antifouling (AF) agents has been pursued in the last years. Sulfur is the third most common element in seawater. Sulfur is present in oxygenated seawater as sulfate anion (SO42−), which is the most stable combination of sulfur in seawater, and several promising AF secondary metabolites with sulfate groups have been described. However, sulfated compounds proved to be an analytical challenge to quantify by HPLC. Taking these facts into consideration, this work presents the development and validation of a method for the quantification of gallic acid persulfate (GAP) in seawater and ultrapure water matrix, based on hydrophilic interaction liquid chromatography (HILIC). This method was used to evaluate GAP stability following several abiotic and biotic degradation assays, and to quantify its release in seawater from room-temperature-vulcanizing polydimethylsiloxane commercial coating. GAP was very stable in several water matrices, even at different pH values and in the presence/absence of marine microorganisms and presented a leaching value lower than 0.5%. This work discloses HILIC as an analytical method to overcome the difficulties in quantifying sulfated compounds in water matrices and highlights the potential of GAP as a promising long-lasting coating.

The development of harmless substances to replace biocide-based coatings used to prevent or manage marine biofouling and its unwanted consequences is urgent. The formation of biofilms on submerged marine surfaces is one of the first steps in the marine biofouling process, which facilitates the further settlement of macrofoulers. Anti-biofilm properties of a synthetic polyphenolic compound, with previously described anti-settlement activity against macrofoulers, were explored in this work. In solution this new compound was able to prevent biofilm formation and reduce a pre-formed biofilm produced by the marine bacterium, Pseudoalteromonas tunicata. Then, this compound was applied to a marine coating and the formation of P. tunicata biofilms was assessed under hydrodynamic conditions to mimic the marine environment. For this purpose, polyurethane (PU)-based coating formulations containing 1 and 2 wt.% of the compound were prepared based on a prior developed methodology. The most effective formulation in reducing the biofilm cell number, biovolume, and thickness was the PU-based coating containing an aziridine-based crosslinker and 2 wt.% of the compound. To assess the marine ecotoxicity impact of this compound, its potential to disrupt endocrine processes was evaluated through the modulation of two nuclear receptors (NRs), peroxisome proliferator-activated receptor γ (PPARγ), and pregnane X receptor (PXR). Transcriptional activation of the selected NRs upon exposure to the polyphenolic compound (10 µM) was not observed, thus highlighting the eco-friendliness towards the addressed NRs of this new dual-acting anti-macro- and anti-microfouling agent towards the addressed NRs.

Neurodegenerative diseases (ND) share common molecular/cellular mechanisms that contribute to their progression and pathogenesis. In this sense, we are here proposing new neuroprotection strategies by using marine-derived compounds as fiscalins. This work aims to evaluate the protective effects of fiscalin derivatives towards 1-methyl-4-phenylpyridinium (MPP+)- and iron (III)-induced cytotoxicity in differentiated SH-SY5Y cells, an in vitro disease model to study ND; and on P-glycoprotein (P-gp) transport activity, an efflux pump of drugs and neurotoxins. SH-SY5Y cells were simultaneously exposed to MPP+ or iron (III), and noncytotoxic concentrations of 18 fiscalin derivatives (0–25 μM), being the cytotoxic effect of both MPP+ and iron (III) evaluated 24 and 48 h after exposure. Fiscalins 1a and 1b showed a significant protective effect against MPP+-induced cytotoxicity and fiscalins 1b, 2b, 4 and 5 showed a protective effect against iron (III)-induced cytotoxicity. Fiscalins 4 and 5 caused a significant P-gp inhibition, while fiscalins 1c, 2a, 2b, 6 and 11 caused a modest increase in P-gp transport activity, thus suggesting a promising source of new P-gp inhibitors and activators, respectively. The obtained results highlight fiscalins with promising neuroprotective effects and with relevance for the synthesis of new derivatives for the treatment/prevention of ND.

Oceans are a rich source of structurally unique bioactive compounds from the perspective of potential therapeutic agents. Marine peptides are a particularly interesting group of secondary metabolites because of their chemistry and wide range of biological activities. Among them, cyclic peptides exhibit a broad spectrum of antimicrobial activities, including against bacteria, protozoa, fungi, and viruses. Moreover, there are several examples of marine cyclic peptides revealing interesting antimicrobial activities against numerous drug-resistant bacteria and fungi, making these compounds a very promising resource in the search for novel antimicrobial agents to revert multidrug-resistance. This review summarizes 174 marine cyclic peptides with antibacterial, antifungal, antiparasitic, or antiviral properties. These natural products were categorized according to their sources—sponges, mollusks, crustaceans, crabs, marine bacteria, and fungi—and chemical structure—cyclic peptides and depsipeptides. The antimicrobial activities, including against drug-resistant microorganisms, unusual structural characteristics, and hits more advanced in (pre)clinical studies, are highlighted. Nocathiacins I–III (91–93), unnarmicins A (114) and C (115), sclerotides A (160) and B (161), and plitidepsin (174) can be highlighted considering not only their high antimicrobial potency in vitro, but also for their promising in vivo results. Marine cyclic peptides are also interesting models for molecular modifications and/or total synthesis to obtain more potent compounds, with improved properties and in higher quantity. Solid-phase Fmoc- and Boc-protection chemistry is the major synthetic strategy to obtain marine cyclic peptides with antimicrobial properties, and key examples are presented guiding microbiologist and medicinal chemists to the discovery of new antimicrobial drug candidates from marine sources.

The growing number of infectious diseases around the world threatens the effective response of antibiotics, contributing to the increase in antibiotic resistance seen as a global health problem. Currently, one of the main challenges in antimicrobial drug discovery is the search for new compounds that not only exhibit antimicrobial activity, but can also potentiate the antimicrobial activity and revert antibiotics’ resistance, through the interference with several mechanisms, including the inhibition of efflux pumps (EPs) and biofilm formation. Inspired by macroalgae brominated bromophenol BDDE with antimicrobial activity, a series of 18 chalcone derivatives, including seven chalcones (9–15), six dihydrochalcones (16–18, and 22–24) and five diarylpropanes (19–21, and 25 and 26), was prepared and evaluated for its antimicrobial activity and potential to fight antibiotic resistance. Among them, chalcones 13 and 14 showed promising antifungal activity against the dermatophyte clinical strain of Trichophyton rubrum, and all compounds reversed the resistance to vancomycin in Enterococcus faecalis B3/101, with 9, 14, and 24 able to cause a four-fold decrease in the MIC of vancomycin against this strain. Compounds 17–24 displayed inhibition of EPs and the formation of biofilm by S. aureus 272123, suggesting that these compounds are inhibiting the EPs responsible for the extrusion of molecules involved in biofilm-related mechanisms. Interestingly, compounds 17–24 did not show cytotoxicity in mouse embryonic fibroblast cell lines (NIH/3T3). Overall, the results obtained suggest the potential of dihydrochalcones 16–18 and 22–24, and diarylpropanes 19–21, 25 and 26, as hits for bacterial EPs inhibition, as they are effective in the inhibition of EPs, but present other features that are important in this matter, such as the lack of antibacterial activity and cytotoxicity.

Sensitive skin is characterized by symptoms such as stinging and tingling in response to stimuli that usually do not cause unpleasant sensations. Epidemiological studies show that individuals with sensitive skin are more prone to developing skin allergies, although the link between both conditions is unknown. Aiming to evaluate the presence of allergens in facial-skin products for sensitive skin, a pool of 88 cosmetic products from international brands marketed in pharmacies and parapharmacies was analyzed. A list of allergens identified in product labels was compiled and grouped according to their function. Fragrances were the most common allergens, followed by skin-conditioning agents, surfactants, and preservatives. Fragrances presenting the highest use percentages were linalool, benzyl alcohol, geraniol, and citronellol. Overall, the majority of cosmetic formulations were absent of fragrance allergens, being present only in 7% of products. Other allergens were found in most products (95%). This finding should be interpreted with caution, since many of these compounds are rare sensitizers and studies demonstrating their risk for individuals with sensitive skin are lacking. With this study, useful information for health professionals is provided to support their advice and to help consumers choosing cosmetic products.

The photoprotective skincare segment is in high demand to meet consumer concerns on UV-induced skin damage, with a recent trend towards sunscreen alternatives with a natural origin. In this study, the use of natural ingredients, either from terrestrial or marine origin, in a panel of 444 sunscreen commercial formulations (2021) was analyzed. Ingredients from terrestrial organisms represent the large majority found in the analyzed sunscreen formulations (48%), whereas marine ingredients are present only in 13% of the analyzed products. A deeper analysis regarding the most prevalent families of ingredients from terrestrial and marine organisms used as top ingredients is also presented, as well as their mechanisms of action. This study provides an up-to-date overview of the sunscreen market regarding the use of natural ingredients, which is of relevance for scientists involved in the development of new sunscreens to identify opportunities for innovation.

The use of sunscreens is an established and recommended practice to protect skin from solar-induced damage. Around 30 UV filters can be used in sunscreen products in the European Union, which ought to follow the requirements of the regulation 1223/2009 to ensure their efficacy and safety for humans. Nevertheless, low photostability and putative toxicity for humans and environment have been reported for some UV filters. Particularly, the negative impact in marine organisms has recently raised concern on the scientific community. Therefore, it is important to develop new UV filters with improved safety profile and photostability. Over the last two decades, nearly 200 new compounds have revealed promising photoprotection properties. The explored compounds were obtained through different approaches, including exploration of natural sources, synthetic pathways, and nanotechnology. Almost 50 natural products and around 140 synthetic derivatives, such as benzimidazoles, benzotriazoles, hydroxycinnamic acids, xanthones, triazines, among others, have been studied aiming the discovery of novel, effective, and safer future photoprotective agents. Herein, we provide the reader with an overview about UV filters’ challenges and prospects, offering a forward-looking to the next-generation of UV filters.

Human skin aging results from intrinsic and extrinsic factors. Uneven pigmentation is one of the major changes of extrinsic aging. Many compounds have been tested for depigmenting activity but only a few are actually used by the cosmetic industry, which is continually looking for new ingredients. In this study, the trends in the use of skin depigmenting ingredients in a panel of anti-aging formulations commercialized in the Portuguese pharmacy market were analyzed, by comparing the composition of the products marketed in 2011 with products launched or reformulated in 2018 (59% and 74%, respectively). The analysis of the top 12 ingredients put forward three novelties for 2018: tranexamic acid, bakuchiol, and 4-butylresorcinol. Regarding their mechanisms of action, tranexamic acid inhibits melanin synthesis through inhibition of the plasminogen/plasmin system. Bakuchiol depigmenting efficacy was attributed to the ability to block both α-melanocyte-stimulating hormone and tyrosinase activation, while 4-butylresorcinol exerts its action through the inhibition of both tyrosinase and tyrosinase-related protein-1 (TRP-1). Industry-optimized and efficient synthetic methodologies that embrace green chemistry, reducing the environmental impact, are commonly used. This analysis aims to bring insights to both formulators, involved in the development of depigmenting cosmetic products, and chemists performing the synthesis of new and existing compounds intended for this purpose.

Doxorubicin (DOX) is a topoisomerase II inhibitor commonly used in the treatment of several types of cancer. Despite its efficacy, DOX can potentially cause fatal adverse effects, like cardiotoxicity. This work aimed to assess the role of inflammation in DOX-treated infant and adult mice and its possible link to underlying cardiotoxicity. Two groups of CD-1 male mice of different ages (infants or adults) were subjected to biweekly DOX administrations, to reach a cumulative dose of 18.0 mg/kg, which corresponds approximately in humans to 100.6 mg/m2 for infants and 108.9 mg/m2 for adults a clinically relevant dose in humans. The classic plasmatic markers of cardiotoxicity increased, and that damage was confirmed by histopathological findings in both groups, although it was higher in adults. Moreover, in DOX-treated adults, an increase of cardiac fibrosis was observed, which was accompanied by an increase in specific inflammatory parameters, namely, macrophage M1 and nuclear factor kappa B (NF-κB) p65 subunit, with a trend toward increased levels of the tumor necrosis factor receptor 2 (TNFR2). On the other hand, the levels of myeloperoxidase (MPO) and interleukin (IL)-6 significantly decreased in DOX-treated adult animals. In infants, a significant increase in cardiac protein carbonylation and in the levels of nuclear factor erythroid-2 related factor 2 (Nrf2) was observed. In both groups, no differences were found in the levels of tumor necrosis factor (TNF-α), IL-1β, p38 mitogen-activated protein kinase (p38 MAPK) or NF-κB p52 subunit. In conclusion, using a clinically relevant dose of DOX, our study demonstrated that cardiac effects are associated not only with the intensity of the inflammatory response but also with redox response. Adult mice seemed to be more prone to DOX-induced cardiotoxicity by mechanisms related to inflammation, while infant mice seem to be protected from the damage caused by DOX, possibly by activating such antioxidant defenses as Nrf2.

Antimicrobial peptides are one of the lines of defense produced by several hosts in response to bacterial infections. Inspired by them and recent discoveries of xanthones as bacterial efflux pump inhibitors, chiral amides with a xanthone scaffold were planned to be potential antimicrobial adjuvants. The chiral derivatives of xanthones were obtained by peptide coupling reactions between suitable xanthones with enantiomerically pure building blocks, yielding derivatives with high enantiomeric purity. Among 18 compounds investigated for their antimicrobial activity against reference strains of bacteria and fungi, antibacterial activity for the tested strains was not found. Selected compounds were also evaluated for their potential to inhibit bacterial efflux pumps. Compound (R,R)-8 inhibited efflux pumps in the Gram-positive model tested and three compounds, (S,S)-8, (R)-17 and (R,S)-18, displayed the same activity in the Gram-negative strain used. Studies were performed on the inhibition of biofilm formation and quorum-sensing, to which the enantiomeric pair 8 displayed activity for the latter. To gain a better understanding of how the active compounds bind to the efflux pumps, docking studies were performed. Hit compounds were proposed for each activity, and it was shown that enantioselectivity was noticeable and must be considered, as enantiomers displayed differences in activity.

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.

Biofouling, which occurs when certain marine species attach and accumulate in artificial submerged structures, represents a serious economic and environmental issue worldwide. The discovery of new non-toxic and eco-friendly antifouling systems to control or prevent biofouling is, therefore, a practical and urgent need. In this work, the antifouling activity of a series of 24 xanthones, with chemical similarities to natural products, was exploited. Nine (1, 2, 4, 6, 8, 16, 19, 21, and 23) of the tested xanthones presented highly significant anti-settlement responses at 50 μM against the settlement of mussel Mytilus galloprovincialis larvae and low toxicity to this macrofouling species. Xanthones 21 and 23 emerged as the most effective larval settlement inhibitors (EC50 = 7.28 and 3.57 µM, respectively). Additionally, xanthone 23 exhibited a therapeutic ratio (LC50/EC50) > 15, as required by the US Navy program attesting its suitability as natural antifouling agents. From the nine tested xanthones, none of the compounds were found to significantly inhibit the growth of the marine biofilm-forming bacterial strains tested. Xanthones 4, 6, 8, 16, 19, 21, and 23 were found to be non-toxic to the marine non-target species Artemia salina (21 and 23 suggest that these two compounds affected similar molecular targets and cellular processes in mussel larvae, including that related to mussel adhesion capacity. This work exposes for the first time the relevance of C-1 aminated xanthones with a 3,4-dioxygenated pattern of substitution as new non-toxic products to prevent marine biofouling.

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respectively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (-)-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. in vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.

Marine-derived fungi constitute an interesting source of bioactive compounds, several of which exhibit antibacterial activity. These acquire special importance, considering that antimicrobial resistance is becoming more widespread. The overexpression of efflux pumps, capable of expelling antimicrobials out of bacterial cells, is one of the most worrisome mechanisms. There has been an ongoing effort to find not only new antimicrobials, but also compounds that can block resistance mechanisms which can be used in combination with approved antimicrobial drugs. In this work, a library of nineteen marine natural products, isolated from marine-derived fungi of the genera Neosartorya and Aspergillus, was evaluated for their potential as bacterial efflux pump inhibitors as well as the antimicrobial-related mechanisms, such as inhibition of biofilm formation and quorum-sensing. Docking studies were performed to predict their efflux pump action. These compounds were also tested for their cytotoxicity in mouse fibroblast cell line NIH/3T3. The results obtained suggest that the marine-derived fungal metabolites are a promising source of compounds with potential to revert antimicrobial resistance and serve as an inspiration for the synthesis of new antimicrobial drugs.

Marine ingredients are a source of new chemical entities with biological action, which is the reason why they have gained relevance in the cosmetic industry. The facial care category is the most relevant in this industry, and within it, the sensitive skin segment occupies a prominent position. This work analyzed the use of marine ingredients in 88 facial cosmetics for sensitive skin from multinational brands, as well as their composition and the scientific evidence that supports their efficacy. Marine ingredients were used in 27% of the cosmetic products for sensitive skin and included the species Laminaria ochroleuca, Ascophyllum nodosum (brown macroalgae), Asparagopsis armata (red macroalgae), and Chlorella vulgaris (microalgae). Carotenoids, polysaccharides, and lipids are the chemical classes highlighted in these preparations. Two ingredients, namely the Ascophyllum nodosum extract and Asparagopsis armata extracts, present clinical evidence supporting their use for sensitive skin. Overall, marine ingredients used in cosmetics for sensitive skin are proposed to reduce skin inflammation and improve the barrier function. Marine-derived preparations constitute promising active ingredients for sensitive skin cosmetic products. Their in-depth study, focusing on the extracted metabolites, randomized placebo-controlled studies including volunteers with sensitive skin, and the use of extraction methods that are more profitable may provide a great opportunity for the cosmetic industry.

A supramolecular atropine sensor was developed, using cucurbit[6]uril as the recognition element. The solid-contact electrode is based on a polymeric membrane incorporating cucurbit[6]uril (CB[6]) as an ionophore, 2-nitrophenyl octyl ether as a solvent mediator, and potassium tetrakis (4-chlorophenyl) borate as an additive. In a MES-NaOH buffer at pH 6, the performance of the atropine sensor is characterized by a slope of (58.7 ± 0.6) mV/dec with a practical detection limit of (6.30 ± 1.62) × 10−7 mol/L and a lower limit of the linear range of (1.52 ± 0.64) × 10−6 mol/L. Selectivity coefficients were determined for different ions and excipients. The obtained results were bolstered by the docking and spectroscopic studies which demonstrated the interaction between atropine and CB[6]. The accuracy of the potentiometric analysis of atropine content in certified reference material was evaluated by the t-Student test. The herein proposed sensor answers the need for reliable methods providing better management of this hospital drug shelf-life while reducing its flush and remediation costs.

Sensitive skin is characterized by symptoms of discomfort when exposed to environmental factors. Peptides are used in cosmetics for sensitive skin and stand out as active ingredients for their ability to interact with skin cells by multiple mechanisms, high potency at low dosage and the ability to penetrate the stratum corneum. This study aimed to analyze the composition of 88 facial cosmetics for sensitive skin from multinational brands regarding usage of peptides, reviewing their synthetic pathways and the scientific evidence that supports their efficacy. Peptides were found in 17% of the products analyzed, namely: acetyl dipeptide-1 cetyl ester, palmitoyl tripeptide-8, acetyl tetrapeptide-15, palmitoyl tripeptide-5, acetyl hexapeptide-49, palmitoyl tetrapeptide-7 and palmitoyl oligopeptide. Three out of seven peptides have a neurotransmitter-inhibiting mechanism of action, while another three are signal peptides. Only five peptides present evidence supporting their use in sensitive skin, with only one clinical study including volunteers having this condition. Noteworthy, the available data is mostly found in patents and supplier brochures, and not in randomized placebo-controlled studies. Peptides are useful active ingredients in cosmetics for sensitive skin. Knowing their efficacy and synthetic pathways provides meaningful insight for the development of new and more effective ingredients.