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Abstract According to The World Alzheimer Report 2023 by Alzheimer’s Disease International (ADI) estimates that 33 to 38.5 million people worldwide suffer from Alzheimer’s Disease (AD). A crucial hallmark associated with this disease is associated with the deficiency of the brain neurotransmitter acetylcholine, due to an affected acetylcholinesterase (AChE) activity. Marine organisms synthesize several classes of compounds, some of which exhibit significant AChE inhibition, such as petrosamine, a coloured pyridoacridine alkaloid. The aim of this work was to characterize the activity of petrosamine isolated for the first time from a Brazilian marine sponge, using two neurotoxicity models with aluminium chloride, as exposure to aluminium is associated with the development of neurodegenerative diseases. The in vitro model was based in a neuroblastoma cell line and the in vivo model exploited the potential of zebrafish (Danio rerio) embryos in mimicking hallmarks of AD. To our knowledge, this is the first report on petrosamine’s activity over these parameters, either in vitro or in vivo, in order to characterize its full potential for tackling neurotoxicity. Graphical Abstract

As the spread of bacterial resistance to clinically available antibiotics has become a global public health problem, the scientific community has intensified its studies in the search for natural compounds and their derivatives to combat bacterial resistance. In this work, a circadian study of the essential oil extracted from the leaves of Croton piauhiensis (EOCP) was carried out. We also sought to evaluate its antibacterial activity, modulatory potential and if it acts as a possible inhibitor of the efflux pump by determining the minimum inhibitory concentration (MIC) and the association of the oil in subinhibitory concentrations with the antibiotic ciprofloxacin and with ethidium bromide (EtBr) against the strain of Staphylococcus aureus K2068 strain. The assays used to obtain the MIC of the EOCP were performed by broth microdilution, while the efflux pump inhibitory test was performed by the MIC modification method. According to the results, the circadian study showed differences in the chemical composition and percentage of oils collected at different times of the day, which can be attributed to environmental conditions. The main components of the EOCP were β-caryophyllene (6 h—21.23%; 12 h—22.86% and 18 h—16.95%), followed by D-Limonene (6 h—13.27% and 18 h—15.95%) and γ-Elemene (12 h)—12.61%). The EOCP collected at 12 h had a better profile in reducing MIC, presenting antibacterial activity for Staphylococcus aureus and Escherichia coli. In the efflux pump test, it was observed that the oil was able to potentiate the action of ethidium bromide against the S. aureus K2068 strain, which can contribute to the prevention or treatment of infectious diseases caused by multidrug-resistant (MDR) strains.

Bacterial resistance is a global health problem that needs to be solved through discovery of new therapeutic strategies. This study aimed to conduct in vitro assays to evaluate intrinsic and modulatory antimicrobial activity of (E)-1-(4-aminophenyl)-3-(4-ethoxyphenyl)prop-2-en-1-one (CPA-Etox) against different efflux pump producing Staphylococcus aureus strains, as well as to perform in silico studies to evaluate its pharmacokinetic properties (ADMET - absorption, distribution, metabolism, excretion, and toxicity) and to use molecular docking technique to identify molecular interactions between the aminochalcone with different efflux pumps (TetK, MepA, QacC, and QacA/B). Microbiological assays were performed using broth microdilution technique. CPA-Etox was tested alone or in combination with different antibacterial agents. CPA-Etox showed no direct antimicrobial activity but enhanced the antibacterial activity of norfloxacin against S. aureus K2068 (expressing mepA) and erythromycin against S. aureus RN-4220 (expressing msrA). CPA-Etox also increased the ethidium bromide activity against S. aureus K4100 (expressing qacC) and S. aureus K4414 (expressing qacA/B). Molecular docking showed the probable binding sites of CPA-Etox with the efflux pumps analyzed. Through in silico studies of pharmacokinetic properties, it was possible to observe that physical–chemical properties of CPA-Etox are within acceptable ADMET parameters, highlighting excellent correlation between the chalcone chemical structure and its pharmacokinetics, based on a high oral bioavailability and low toxicity response by ingestion. These results will be relevant for definition of possible CPA-Etox technological applications as an adjuvant to traditional antimicrobial agents in the treatment of staphylococcal infections caused by S. aureus strains expressing efflux pump genes.

Treatment of cutaneous leishmaniasis depends on drugs that potentially cause serious side effects and resistance. Thus, topical therapies are attractive alternatives to the drugs currently used. 3β, 6β, 16β-trihydroxylup-20 (29)-ene is a lupane triterpene isolated from Combretum leprosum Mart. leaves (CLF-1), with reports of in vitro antileishmanial effect against L. amazonensis and to promote lesion healing in animal model. Herein, we evaluated the in vitro and in vivo antileishmanial and healing effects of CLF-1 against L. braziliensis. CLF-1 treatment showed low toxicity in macrophages and significantly reduced parasite load in vitro. CLF-1 induced higher IL-12 and TNF-α production and more discrete IL-4 and IL-10 production. For in vivo evaluation, a CLF-1 cream formulation was prepared to treat hamsters infected with L. braziliensis. CLF-1 treatment was able to reduce parasite load of the infected skin and lymph node more efficiently than the conventional treatment. Histopathological analysis indicated a strong inflammatory response accompanied by an important healing response. Data from this study indicate that topical CLF-1 treatment was effective and non-toxic in L. braziliensis infected hamsters suggesting its potential for further development as a future therapeutic intervention.

Abstract Background The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19. Results Molecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood–brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1–T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target. Conclusions Hybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19.

As chalconas são moléculas orgânicas encontradas na natureza em diversas famílias de plantas e com relevância para o mercado químico-farmacológico. Não obstante, a molécula sintética N-{(4’-[(E)-3-3(4-fluorofenil)-1-(fenil)prop-2-em-1-ona]}acetamida (PAAPFBA) também contribui em tais preceito, pois apresenta em sua constituição, atividade ansiolítica e antioxidante. Dadas as potencialidades da PAAPFBA e seus atributos na contemporaneidade, o estudo tem por finalidade investigar em caráter in silico uma possível atividade inseticida e seus impactos sob as abelhas da espécie Apis melífera, visto que, os insumos agrícolas industriais utilizados ocasionam detrimento destes organismos, assim como, impactos à saúde humana. A metodologia foi baseada em métodos QSAR (Quantitative Structure-Activity Relationship) com ênfase nas plataformas InsectiPAD: Insecticide Physicochemical-properties Analysis Database© e BeeToxAI©. A partir da utilização desses métodos pode-se inferir que a chalcona PAAPFBA apresenta alto potencial inseticida e não ocasiona toxicidade aguda por via oral ou contato em abelhas do gênero Apis melífera o que pode contribuir para que novas moléculas desta classe de compostos possam ser introduzidas no mercado agroindustrial. Todavia, ainda se faz necessário a incorporação de diversos ensaios em diferentes compartimentos ambientais (água, sedimento e solo) para investigar seus possíveis impactos nestes locais buscando a efetividade, segurança e saúde ambiental.

Species belonging to the genus Lippia are used worldwide as foods, beverages, and seasonings. Studies have demonstrated that these species have antioxidant, sedative, analgesic, anti-inflammatory, and antipyretic activities. This work aimed to evaluate the antibacterial activity and anxiolytic effect by different pathways of essential oils and ethanolic extracts of three species of Lippia (Lippia alba, Lippia sidoides, and Lippia gracilis). The ethanolic extracts were characterized by HPLC-DAD-ESI-MSn and their phenolics were quantified. The antibacterial activity was evaluated by determining the minimal inhibitory concentration and modulation of antibiotic activity, and toxic and anxiolytic effects were evaluated in the zebrafish model. The extracts showed compositions with a low ratio and shared compounds. L. alba and L. gracilis showed higher amounts of phenols and flavonoids, respectively. All extracts and essential oils presented antibacterial activity, especially those obtained from L. sidoides. On the other hand, L. alba extract presented the most significant antibiotic-enhancing effect. The samples were not toxic after 96 h of exposure, but showed an anxiolytic effect through modulation of the GABAA receptor, while L. alba extract acted via modulation of the 5-HT receptor. This new pharmacological evidence opens horizons for therapeutic approaches targeting anxiolytic and antibacterial therapies and food conservation using these species and their constituents.

RESUMO O objetivo deste trabalho foi avaliar o perfil químico, teor de fenóis totais e as atividades antioxidante, antiacetilcolinesterásica e antifúngica dos extratos etanólicos das folhas (EEF) e do caule (EEC) de cinco espécies de Senna, bem como avaliar a correlação entre o conteúdo de fenóis totais com a atividade sequestradora do radical livre DPPH e com a inibição da enzima acetilcolinesterase AChEI. No teste fitoquímico, evidenciou-se a presença de metabólitos secundários em todos os extratos. Os EEF e EEC de Senna trachypus, destacaram-se por apresentar os maiores valores de fenóis totais. Os EEF e EEC de S. trachypus mostraram a melhor ação sobre a enzima acetilcolinesterase. Todas as espécies apresentaram atividade antioxidante, em especial o EEF de S. trachypus. Foi observado correlação forte para as variáveis fenóis totais e atividade antioxidante (r = -0,71), muito forte para fenóis totais e antiacetilcolinesterase (r = -0,84) e atividade moderada para atividade antioxidante e antiacetilcolinesterase (0,43). Apenas os extratos de S. trachypus apresentaram atividade contra todos os dermatófitos, quando comparado às demais espécies. A espécie S. trachypus foi considerada a planta mais promissora para estudos subsequentes, a fim de encontrar compostos com ações farmacológicas.

A large number of infections are caused by multi-resistant bacteria worldwide, adding up to a figure of around 700,000 deaths per year. Because of that many strategies are being developed in order to combat the resistance of microorganisms to drugs, in recent times, chalcones have been studied for this purpose. Chalcones are known as α, β-unsaturated ketones, characterized by having the presence of two aromatic rings that are joined by a three-carbon chain, they are a class of compounds considered an exceptional model due to chemical simplicity and a wide variety of biological activities, which include anticancer, anti-inflammatory, antioxidants, antimicrobials, anti-tuberculosis, anti-HIV, antimalarial, anti-allergic, antifungal, antibacterial, and antileishmanial. The objective of this work was evaluate the antibacterial and antibiotic modifying activity of chalcone (E)-1-(2-hydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)prop-2-en-1-one against the bacteria Staphylococcus aureus carrying a NorA and MepA efflux pump. The results showed that chalcone was able to synergistically modulate the action of Norfloxacin and Ethidium Bromide against the bacteria Staphylococcus aureus 1199B and K2068, respectively. The theoretical physicochemical and pharmacokinetic properties of chalcone showed that the chalcone did not present a severe risk of toxicity such as genetic mutation or cardiotoxicity, constituting a good pharmacological active ingredient.

RESUMO Este artigo de revisão reporta ao estudo químico e farmacológico de metabolitos secundários isolados de 20 espécies do gênero Zanthoxylum Linnaeus. Os constituintes químicos voláteis e fixos das espécies desse gênero foram isolados e caracterizados por métodos analíticos. Esta revisão foi realizada através da busca organizada de Dissertações de Mestrado, Teses de Doutorado e principalmente artigos científicos publicados sobre estudos fotoquímicos e atividades antimicrobianas das espécies do gênero Zanthoxylum disponíveis nos Periódicos CAPES, PubMed, ScienceDirect, Scopus, Scielo e Google Acadêmico entre 1985 e 2019. As espécies apresentaram composição química diversificada onde predominam alcaloides, terpenos e cumarinas com diferentes tipos de atividades antimicrobianas, tais como: antifúngica, antibiótica, antiprotozoário e antiviral.

Abstract: This article describes the chemical composition of Vernonia chalybaea essential oil, and investigates its antimicrobial, antioxidant and hemolytic activities. The evaluation of the antifungal activity was performed by the broth microdilution method using strains of yeasts and dermatophytic fungi. The checkerboard technique to find antimicrobial modulatory effects was performed using ketoconazole as standard drug. The antioxidant activity was evaluated by DPPH scavenging assay and β-carotene/linoleic-acid system. The toxicity was characterized by the brine shrimp lethality test and hemolysis bioassays. The essential oil was obtained by hydrodistillation and analyzed by GC-MS method, showing to be rich in the sesquiterpenes β-caryophyllene (39.06%) and bicyclogermacrene (19.69%), and also demonstrated a relevant antifungal activity against strains of Trichophyton rubrum. In the modulatory activity assay, the essential oil of V. chalybaea and β-caryophyllene demonstrated a synergistic interaction with ketoconazole, with increasing of its antifungal action. The antioxidant activity was evidenced mainly by β-carotene/linoleic acid system, with IC50 value of 35.87 ± 0.32 µg/mL. The results suggest that V. chalybaea essential oil and β-caryophyllene are valuable natural medicinal agents with antioxidant and antimicrobial activities.

RESUMO Compostos químicos com atividades biológicas isolados de espécies vegetais e usados pela população por meio de extratos e óleo essencial são promissoras fontes de prospecção de novos fármacos. O gênero Myroxylon L. f. apresenta elevado potencial farmacológico, sendo usado na medicina popular para o tratamento de diversas enfermidades, tais como feridas, catarros, úlceras, dores de cabeça e de ouvido. Este artigo de revisão apresenta as principais características fitoquímicas e farmacológicas das espécies do gênero Myroxylon (M. peruiferum L.f., M. balsamum (L.) Harms e M. pereirae (Royle) Klotzsch), cujos estudos de atividades biológicas são promissores.

Background: Chalcones are part of a family of small phenolic compounds that are being extensively studied for presenting a diversity of molecular structures and biological activities. In this paper, two chalcones, (E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one (1), (E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (2), were synthesized by Claisen–Schmidt condensation. Methods: The molecular structures of these chalcones were determined by Nuclear Magnetic Resonance and characterized by infrared, Raman spectroscopy, and electrochemical analysis at room temperature. Vibrational wavenumbers were predicted using Functional Density Theory (DFT) calculations, and their normal modes were analyzed in terms of potential energy distribution (PED). Besides this, DFT calculations were performed to obtain the molecular orbitals and their quantum descriptors. The UV-Vis absorption spectrum of the synthesized chalcones was measured and compared with each other. In addition, analyses of antimicrobial activity and modulation of antibiotic resistance were carried out to assess the antibacterial potential of these chalcones. Results: The vibrational spectra of polycrystalline chalcones obtained by ATR-FTIR, FT-Raman and DFT calculations allowed a complete assignment of the vibrational modes, and revealed the quantum chemical parameters. Both chalcones did not show good responses when associated with the antibiotics Ciprofloxacin and Cephalexin against S. aureus 10 and E. coli 06 strains. However, a significant potentiating of the Gentamicin activity against S. aureus 10 and E. col 06 strains was observed for chalcone 2. On the other hand, when associated with Norfloxacin, an antagonistic effect was observed. The results found for EtBr suggest that, although the tested chalcones behave as efflux pump inhibitors, probably inhibiting other efflux pumps, they were not able to inhibit NorA. Thus, these synthetic chalcones are not recommended for use in association with Norfloxacin against strains of S. aureus 1199-B that overexpress the NorA gene. Conclusions: Spectroscopic data confirmed the structure of the chalcones, and chalcone 2 showed potential as an adjuvant in antibiotic therapy.

The study investigated the antimicrobial activity of the essential oil extract of Ocimum gratissimum L. (EOOG) against multiresistant microorganisms in planktonic and biofilm form. Hydrodistillation was used to obtain the EOOG, and the analysis of chemical composition was done by gas chromatography coupled with mass spectrometry (GC/MS) and flame ionization detection (GC/FID). EOOG biological activity was verified against isolates of Staphylococcus aureus and Escherichia coli, using four strains for each species. The antibacterial action of EOOG was determined by disk diffusion, microdilution (MIC/MBC), growth curve under sub-MIC exposure, and the combinatorial activity with ciprofloxacin (CIP) and oxacillin (OXA) were determined by checkerboard assay. The EOOG antibiofilm action was performed against the established biofilm and analyzed by crystal violet, colony-forming unit count, and SEM analyses. EOOG yielded 1.66% w/w, with eugenol as the major component (74.83%). The MIC was 1000 µg/mL for the most tested strains. The growth curve showed a lag phase delay for both species, mainly S. aureus, and reduced the growth level of E. coli by half. The combination of EOOG with OXA and CIP led to an additive action for S. aureus. A significant reduction in biofilm biomass and cell viability was verified for S. aureus and E. coli. In conclusion, EOOG has relevant potential as a natural alternative to treat infections caused by multiresistant strains.

The chemical investigation of hexane and ethanol extracts from the aerial parts of Vernonia scorpioides resulted in the isolation and characterization of a new polyacetylene lactone, rel-4-dihydro-4β-hydroxy-5a-octa-2,4,6-triynyl-furan-2-(5H)-one, along with the new ethyl 3,4-dihydroxy-6,8,10-triynyl-dodecanoate, and seven known compounds: taraxasteryl acetate, lupeyl acetate, lupeol, lupenone, β-sitosterol, stigmasterol and luteolin. The structure of all compounds was determined by spectrometric techniques (HR-ESI-MS, ¹H and 13C NMR and IV) and comparison with published spectral data.

Croton nepetaefolius is a native plant from northeastern Brazil that belongs to the Euphorbiaceae family. The biological action of this plant has been extensively explored, being the secondary metabolites responsible for its properties alkaloids, diterpenes, and triterpenes. This study aimed to evaluate the ability of casbane diterpene (CD), isolated from the ethanolic extract of C. nepetaefolius, to inhibit microbial growth and biofilm formation of several clinical relevant species (bacteria and yeasts). It was found that CD possessed biocidal and biostatic activity against the majority of the species screened, with minimal active concentrations ranging between 125 and 500 µg/mL. In addition, it was observed that biofilm formation was inhibited even when the planktonic growth was not significantly affected. In conclusion, CD showed potential to be a natural tool for the treatment of diseases caused by different infectious microorganisms.

The phytochemical investigation of the ethanol extract from the aerial parts of Blainvillea rhomboidea (Asteraceae) resulted in the isolation and characterization of 8β-tigloyloxy-grazielia acid, together with the flavonoids derrone, acacetin, luteolin and luteolin 7-methyl ether, and p-(1-methyl-ethan-1-ol)-phenol. The structures of all compounds were determined by spectroscopic methods (¹H and 13C NMR and HREIMS) and comparison with published spectral data. The flavonoids luteolin and 7-O-metyl-luteolin, isolated from the active dichloromethane fraction, showed moderate cytotoxic activity.

Croton nepetaefolius is an aromatic plant native to the northeast of Brazil where it is extensively used in folk medicine as a sedative, orexigen and antispasmodic agent. The present work deals with the chromatographic analysis of the ethanolic extract of Croton nepetaefolius stalk. It allowed the isolation and characterization of two diterpenoids named 1,4-dihydroxy-2E,6E,12E-trien-5-one-casbane and 4-hydroxy-2E,6E,12E-5-one-casbane, two acetophenones named 2-hydroxy-4,6-dimethoxyacetophenone and 2-hydroxy-3,4,6-trimethoxyacetophenone and the steroids 3-O-b-D-glucopiranosylsitosterol and a mixture of b-sitosterol and stigmasterol. Structural elucidation was done on the basis of spectral data, mainly high field NMR and EIMS.