Fungal biofilms as a valuable target for the discovery of natural products that cope with the resistance of medically important fungi—Latest findings

The development of new antifungal agents that target biofilms is an urgent need. Natural products, mainly from the plant kingdom, represent an invaluable source of these entities. The present review provides an update (2017–May 2021) on the available information on essential oils, propolis, extracts from plants, algae, lichens and microorganisms, compounds from different natural sources and nanosystems containing natural products with the capacity to in vitro or in vivo modulate fungal biofilms. The search yielded 42 articles; seven involved essential oils, two Brazilian propolis, six plant extracts and one of each, extracts from lichens and algae/cyanobacteria. Twenty articles deal with the antibiofilm effect of pure natural compounds, with 10 of them including studies of the mechanism of action and five dealing with natural compounds included in nanosystems. Thirty‐seven manuscripts evaluated Candida spp. biofilms and two tested Fusarium and Cryptococcus spp. Only one manuscript involved Aspergillus fumigatus. From the data presented here, it is clear that the search of natural products with activity against fungal biofilms has been a highly active area of research in recent years. However, it also reveals the necessity of deepening the studies by (i) evaluating the effect of natural products on biofilms formed by the newly emerged and worrisome health‐care associated fungi, C. auris, as well as on other non‐albicans Candida spp., Cryptococcus sp. and filamentous fungi; (ii) elucidating the mechanisms of action of the most active natural products; (iii) increasing the in vivo testing.Fil: Butassi, Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Svetaz, Laura Andrea. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Carpinella, Maria Cecilia. Universidad Católica de Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Recursos Naturales y Sustentabilidad José Sanchez Labrador S. J.; ArgentinaFil: Efferth, Thomas. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Zacchino, Susana Alicia Stella. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentin

Estudos farmacobotânicos comparativos e utilizações ethnopharmacológicas do "botões d'ouro" da medicina popular Argentina

The aerial parts of six Argentinean plants - commonly known as "botones de oro"-are indistinctly used either in folk medicine or to obtain herbal remedies and phytotherapics. However, these entities belong to three different genera of the Tribe Helenieae (Asteraceae): Gaillardia, Helenium and Hymenoxys, being the most used species Gaillardia megapotamica var. megapotamica (Spreng.) Bak.; G. megapotamica var. scabiosoides (Arn.) Bak.; G. megapotamica var. radiata (Griseb.) Bak.; Helenium donianum (Hook. & Arn.) Seckt; H. argentinum Ariza and Hymenoxys anthemoides (Juss.) Cass. In this work, we studied the relationships between the mentioned taxa from the morphological point of view, their coexistence in natural populations and their reputed pharmacological actions. Their histological features are described and illustrated, in order to obtain an accurate botanical identification of the products found in the market so as to guarantee their quality, especially because the samples are often already powdered or grounded.As partes aéreas de seis plantas argentinas - conhecidas geralmente como “botões d’ouro” - são usadas indistintamente na medicina popular ou para obter remédios ervais e fitoterápicos. No entanto, estas entidades pertencem a três gêneros da tribo Helenieae (Asteraceae): Gaillardia, Helenium e Hymenoxys, sendo as espécies mais utilizadas Gaillardia megapotamica var. megapotamica (Spreng.) Bak.; G. megapotamica var. scabiosoides (Arn.) Bak.; G. megapotamica var. radiata (Griseb.) Bak.; Helenium donianum (Hook. & Arn.) Seckt; H. argentinum Ariza e Hymenoxys anthemoides(Juss.) Cass. Neste trabalho, foram estudadas as relações entre os táxons mencionados a partir do ponto de vista morfológico, a sua coexistência em populações naturais e suas ações farmacológicas reputadas. As suas características histológicas são descritas e ilustradas, a fim de obter uma exata identificação botânica dos produtos encontrados no mercado, de forma a garantir a sua qualidade, especialmente porque as amostras são freqüentemente já pulverizadas ou em pó.Fil: Gette, Maria de Los Angeles. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Luis; ArgentinaFil: Petenatti, Marta Elena. Universidad Nacional de San Luis; ArgentinaFil: del Vitto, Luis Angel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Luis; ArgentinaFil: Zacchino, Susana Alicia Stella. Universidad Nacional de Rosario; ArgentinaFil: Petenatti, Elisa Margarita. Universidad Nacional de San Luis; Argentin

Design of two alternative routes for the synthesis of naftifine and analogues as potential antifungal agents

Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues 16 and 20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, theγ-aminoalcohols 15 and 19 were obtained as the key intermediates and their subsequent dehydration catalyzed either by Brønsted acids like H2SO4 and HCl or Lewis acid like AlCl3, respectively, led to naftifine, along with the target allylamines 16 and 20. The antifungal assay results showed that intermediates 18 (bearing both a β-aminoketo- and N-methyl functionalities in their structures) and products 20 were the most active. Particularly, structures 18b, 18c, and the allylamine 20c showed the lowest MIC values, in the 0.5-7.8 μg/mL range, against the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Interesting enough, compound 18b bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against Candida albicans and Cryptococcus neoformans with MIC80 = 7.8 μg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 μg/mL against C. neoformans.Fil: Abonia, Rodrigo. Universidad del Valle; ColombiaFil: Garay, Alexander. Universidad del Valle; ColombiaFil: Castillo, Juan C.. Universidad del Valle; Colombia. Universidad Pedagógica y Tecnológica de Colombia; ColombiaFil: Insuasty, Braulio. Universidad del Valle; ColombiaFil: Quiroga, Jairo. Universidad del Valle; ColombiaFil: Nogueras, Manuel. Universidad de Jaén; EspañaFil: Cobo, Justo. Universidad de Jaén; EspañaFil: Butassi, Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Zacchino, Susana Alicia Stella. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentin

Essential Oil of Azorella cryptantha Collected in Two Different Locations from San Juan Province, Argentina: Chemical Variability and Anti-Insect and Antimicrobial Activities

Essential oils of two populations of Azorella cryptantha (Clos) Reiche, a native species from San Juan province, were obtained by hydrodistillation in a Clevenger-type apparatus and characterized by GC/FID and GC/MS. The compounds identified were 92.3% and 88.7% for A. cryptantha from Bauchaceta and A. cryptantha from Agua Negra respectively. The essential oil composition was similar for both populations with differences in the main components, and in the identity of minor components. The main components of A. cryptantha-BAU essential oil were sabinene (4), betha pinene (5) and delta-cadinol (38) while α-thujene (1), alpha pinene (2), bethe pinene (5) and, delta cadinene (29) were the main monoterpene hydrocarbons in A. cryptantha-AN essential oil wih the addition of 3.0% of oxygenated monoterpenes. Repellent activity on T. infestans nymphs was 100% and 92% for A. cryptantha-AN and A. cryptantha-BAU essential oils respectively. Regarding the toxic effects on C. capitata, the oils were very active with LD50 values of less than 11 µg/fly. Microsporum gypseum, Trichophyton rubrum and T. mentagrophytes and bacteria LM1-E. coli, LM2-E. coli and PI-Yersinia enterocolitica were more sensitive toward the species collected in Agua Negra (MIC equal 125μg/ml). This is the first report on the anti-insect and antimicrobial properties of A. cryptantha essential oil and its composition.Fil: Lopez, Sandra. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; ArgentinaFil: Lima, Beatriz Viviana. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; ArgentinaFil: Aragon, Liliana. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; ArgentinaFil: Ariza Espinar, Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Tapia, Aníbal Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Nacional de San Juan. Facultad de Ingeniería. Instituto de Biotecnología; ArgentinaFil: Zacchino, Susana Alicia Stella. Universidad Nacional de Rosario; ArgentinaFil: Zygadlo, Julio Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Feresin, Gabriela Egly. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: López, María Liza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; Argentin

New limonene-hybrid derivatives with anti-T. cruzi activity

The development of hybrid compounds containing limonene- and recognized anti-T. cruzi-heterocycle-frameworks is described. The six new compounds displayed broad antitrypanosomal activities having 5-nitrofuran and 5-nitroindazole derivatives, the best profiles. In addition, a 5-nitroindazole derivative evaluated against a panel of fungi exhibited relevant activities. Knowing that free-radical-production operates as one of the mechanisms of action on these heterocycles, we studied a potential extra-mechanism, membrane-sterols changes. Non-relevant T. cruzi squalene accumulation was observed for any of the tested hybrid-limonene derivatives. © 2010 Bentham Science Publishers Ltd.Fil: Alvarez, Guzmán. Universidad de la República; UruguayFil: Gerpe, Alejandra. Universidad de la República; UruguayFil: Benitez, Diego. Universidad de la República; UruguayFil: Garibotto, Francisco Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Zacchino, Susana Alicia Stella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Graebin, Cedric Stephan. Universidade Federal do Rio Grande do Sul; BrasilFil: Gomes da Rosa, Ricardo. Universidade Federal do Rio Grande do Sul; BrasilFil: Eifler Lima, Vera. Universidade Federal do Rio Grande do Sul; BrasilFil: González, Mercedes. Universidad de la República; UruguayFil: Cerecetto, Hugo. Universidad de la República; Urugua

Validation of the Ethnopharmacological Use of Polygonum persicaria for its Antifungal Properties

Polygonum L. genus (Polygonaceae) is represented in Argentina by 21 species and some of them have been used in the traditional medicine of our country to treat affections related with fungal infections, such as skin ailments and vaginal diseases. With the aim of contributing to the correct ethnopharmacological use of this genus, in the present work we describe the antifungal properties of P. persicaria (species not studied up to now) and the bio-guided isolation of the main active compounds. Results showed that dichloromethane extracts was the most active with MICs (Minimun Inhibitory Concentrations) between 31.2 – 1000 µg/mL, validating the ethnopharmacological use of P. persicaria to treat affections related with fungal infections in the Argentinean traditional medicine.Fil: Derita, Marcos Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; ArgentinaFil: Zacchino, Susana Alicia Stella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentin

Influence of plant part, season of collection and content of the main active constituent, on the antifungal properties of Polygonum acuminatum Kunth

Ethnopharmacological relevance: Polygonum acuminatum Kunth. (Polygonaceae) is used to heal infected wounds and as antifungal in the traditional Argentinean medicine. Aim of the study: The present investigation was carried out to evaluate the antifungal properties of aerial parts of Polygonum acuminatum, in order to give support to its ethnopharmacological use as antifungal agent and to isolate the compound(s) responsible for the antifungal properties. The influence of the plant part used, the season of the year and a study of the correlation of the antifungal activity with the content of the main active constituent were investigated too, with the aim of contributing to determine the most suitable plant extract and season of the year for achieving the best antifungal properties for Polygonum acuminatum traditional use. Materials and methods: For the antifungal evaluation, the microbroth dilution assay recommended by the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) was used against a panel of human opportunistic and pathogenic fungi. Bioassay-guided fractionation allowed us to isolate the compounds responsible for the antifungal activity. GC-MS was used to quantify the main component in the different extracts. For the statistical analysis, ANOVA test for analyses of variance followed by the Tukey test of Multiple Comparisons were used. The correlations between content of the antifungal compound and antifungal activity, were calculated with the Spearman Correlation Coefficient. Results: Aerial parts (A) of Polygonum acuminatum showed to possess antifungal properties against yeasts as well as dermatophytes but not against Aspergillus spp. From the most active extract (ADCM), polygodial, isopolygodial, drimenol and confertifolin were isolated, possessing polygodial a broader spectrum of action and lower MICs than the rest of compounds. Among the different parts, leaves (L), stems (S) and fruits (F), that constitute the aerial parts of Polygonum acuminatum, (L) showed to possess the best activities, compared to (S) and (F). The analysis of the content of polygodial in the LHex, LDCM, LEtOAC, LMeOH extracts collected in Summer, Autumn, Winter and Spring showed that LDCM of all seasons possessed higher percentages of this sesquiterpene than the rest of extracts. Among the LDCM of different seasons, that of Autumn was the most concentrated in polygodial. The correlation between content of polygodial with antifungal behavior of the different extracts, showed that LDCM of Autumn contains the highest content of polygodial and concomitantly the lowest MICs. Conclusion: The ethnopharmacological use of Polygonum acuminatum aerial parts in the Argentinean traditional medicine for ailments related to fungal infections is supported by the results obtained in this investigation. From the obtained results, LDCM of Autumn, possessing the highest content of polygodial and the lowest MICs, appeared to be the most suitable extract for being used as antifungal in the traditional medicine. Nevertheless, if some other plant collection of another season different from Autumn is available, a LDCM extract would be the better option, because it contains a higher amount of polygodial compared to LHex, LEtOAc or LMeOH and therefore, a better antifungal activity can be expected.Fil: Derita, Marcos Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; ArgentinaFil: Leiva, M. L.. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Zacchino, Susana Alicia Stella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentin

Highly enantioselective reduction of the C-C double bond of N-phenyl-2-methyl- and N-phenyl-2,3-dimethyl-maleimides by fungal strains

The CAC double bond of non-substituted and substituted maleimides were hydrogenated to the corresponding succinimides by fungal strains. 2- and 2,3-methylated-phenyl-maleimides were enantioselectively reduced to (R)-N-phenyl-3-methylsuccinimide and to trans-(R,R)-N-phenyl-2,3-dimethylsuccinimide respectively by Aspergillus niger, A. flavus and A. fumigatus (conversion 96 to 99%), Fusarium graminearum and Penicillium sp (conversion: 37 and 39%), with 99% ee.Fil: Sortino, Maximiliano Andrés. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cechinel Filho, Valdir. University of the Itajaí Valley; BrasilFil: Zacchino, Susana Alicia Stella. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentin

Diferentes estrategias para la búsqueda de compuestos antifúngicos: Síntesis química y biotransformaciones como herramientas para la obtención de compuestos para la actividad antifúngica

El incremento de pacientes inmunocomprometidos y los numerosos inconvenientes de las drogas antifúngicas existentes actualmente en el mercado farmacéutico crean una urgente necesidad del descubrimiento de nuevas drogas para el tratamiento de las micosis. Entre las numerosas familias de compuestos que han sido evaluados con este objetivo, maleimidas N-sustituidas han demostrado ser excelentes candidatos para la generación de una nueva familia de antimicóticos. Por este motivo, un amplio panel de maleimidas y análogos fueron obtenidos y evaluados por su actividad antifúngica. La obtención fue realizada por síntesis química y por biotransformación, estrategia que demostró ser útil para la generación de compuestos activos y para la síntesis diastereo- y enantioespecífica. La actividad se determinó por metodologías estandarizadas, complementada con la evaluación del poder fungicida, espectro de especies susceptibles, mecanismo de acción y de la estabilidad de los compuestos. El análisis de la relación estructura-actividad permitió identificar los requisitos estructurales necesarios para la actividad y seleccionar los compuestos más promisorios para el desarrollo de nuevos antifúngicos.Fil: Sortino, Maximiliano Andrés. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; ArgentinaFil: Derita, Marcos Gabriel. Universidad Nacional del Litoral. Facultad de Ciencias Agrarias. Departamento de Producción Vegetal. Cátedra de Cultivos Intensivos; ArgentinaFil: Zacchino, Susana Alicia Stella. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentin