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Anacardium occidentale (Anacardiaceae), popularly known as cashews, is a vegetable native to South America, consumed worldwide in the food sector. Its leaves and bark are used in the preparation of teas for health maintenance, being indicated in ethnobotanical studies for the treatment of cancer, which is considered a serious public health problem worldwide. The objective of this study was to evaluate the cytotoxicity of the A. occidentale leaf and bark extracts over tumor and normal cells, as well as their in vivo toxicity using the Drosophila melanogaster fruit fly. Cytotoxicity was evaluated using the MTT method [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol bromide] in five cell lines (HL-60, NCI-H292, HCT-116, P815 and L929). Toxicity was evaluated by fly mortality rate and negative geotaxis, as well as by oxidative stress markers (Fe2+ quantification, protein and non-protein thiols) in the D. melanogaster model. The chromatographic study was performed by UPLC-QTOF/MS. As a result, 11 compounds present in the A. occidentale leaf extract (LEAo) and 6 compounds in the bark extract (BEAo) were identified, with gallic acid and galloyl hexoside being present in both samples. The bark extract presented a greater cytotoxic activity for HCT-116, HL60 and P815 tumor cells. The extracts also presented a low cytotoxicity with the normal cell line, L929. No changes in the levels of protein and non-protein thiols (NPSH) were observed, whereas a considerable increase in Fe2+ levels was observed in the Fe2+ quantification assays from homogenized flies exposed to the leaf extract in the D. melanogaster assays. However, further in-depth studies need to be carried out to elucidate the mechanisms of action of the extracts and to assess their pharmacological safety.

Mercury chloride (HgCl2) acts as a bioaccumulator capable of causing numerous neurological and physiological changes in organisms in a negative way. However, rutin has been considered a very effective antioxidant compound in the treatment of neurodegenerative diseases, as it can neutralize radicals capable of damaging neuronal cells. In this context, this study aimed to evaluate rutin as a neoprotective agent against the damage induced by HgCl2 in Drosophila melanogaster. The exposure of the flies to the agents was carried out in triplicate, and about 150 adult flies were evaluated. To assess the antioxidant action of rutin, MTT, phenanthroline, nitric oxide, total thiols and NPSH tests were carried out in the following concentrations: Control (1500 μL of distilled water), 1 mg/g of HgCl2, 0.5 mg/g of Rutin + HgCl2, 1 mg/g of Rutin + HgCl2, 2 mg/g of Rutin + HgCl2. The locomotion test was verified by negative geotaxis, the result of which showed that flies exposed to HgCl2 had difficulties in flight. The group treated with HgCl2 alone had a high mortality rate, while in combination with different concentrations of rutin, it heard a moderate reduction in the number of deaths, as well as in the negative geotaxis data in which the rutin had a positive effect. An increase in iron (II) levels was observed at the highest concentrations of rutin, while at low concentrations, rutin significantly decreased nitric oxide levels. The HgCl2 + R group (2 mg/g) showed a significant increase in the total thiols content, while for the NPSH all rutin concentrations showed a significant increase in the levels of non-protein thiols. Our results demonstrate that mercury chloride can cause oxidative stress in D. melanogaster. However, the results suggest that rutin has antioxidant and protective effects against the damage caused by HgCl2.

Compounds capable of inhibiting the efflux pump mechanism are a promising alternative against bacterial resistance because, when combined with antibiotics, they can increase the effectiveness of these drugs by inhibiting active efflux. Elaiophylin, derived from Streptomyces hygroscopicus, is a natural antibiotic that exhibits a variety of biological activities, including antibacterial activity. However, its potential as an inhibitor of the bacterial efflux mechanism has not been investigated. This study evaluated the ability of Elaiophylin to inhibit the NorA efflux pump in Staphylococcus aureus strains. Therefore, tests were performed to obtain the Minimum Inhibitory Concentration (MIC) and to verify the ability of Elaiophylin to potentiate the MIC of the antibiotic Norfloxacin and Ethidium Bromide (EtBr), known substrates of NorA efflux. Real-time PCR and molecular docking assays were also performed to assess the potential of Elaiophylin against NorA. The strains SA-1199 (wild type) and SA-1199B (NorA over-expressed) of S. aureus were used for this study. The results showed that Elaiophylin significantly decreased the MIC of Norfloxacin and EtBr, increasing the activity of these substrates against S. aureus, which carries the efflux protein NorA. However, Elaiophylin provided a non-significant reduction in norA gene expression, however, molecular docking demonstrated a high binding affinity between Elaiophylin and NorA efflux protein, indicating that Elaiophylin can act as a potential NorA in S. aureus.

The barks of Anacardium occidentale (cashew tree) been used for centuries in the popular pharmacopoeia of South America and West Africa for the treatment of infections and neurodegenerative diseases. Thus, this work aimed to evaluate the biological effect of the ethanolic extract of the barks against strains of Candida spp. and cancer cell lines, as well as identifying the chemical constituents present in the product. For that, the extract was submitted to an UPLC-QTOF/MS, which mass fragments were compared in the literature at the botanical family level. For antifungal activity, the serial microdilution method was used in varying concentrations, and the modifier of fluconazole in sub-inhibitory concentrations (CFM/16). Cytotoxicity was evaluated using the MTT method [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol bromide] in five cell lines (HL-60, NCI-H292, HCT-116, P815 and L929). Eight compounds were identified, including gallic acid, luteolin, epicatechin gallate and agathisflavone. An antifungal effect of the extract was observed for the strains of Candida albicans, Candida krusei and Candida tropicalis, with IC50 lower than 400 μg/mL. In addition, there was a synergistic action with fluconazole against C. albicans and C. tropicalis. As for antitumor activity, there was a moderate activity against all cancer lines, showing low cytotoxicity for the normal line, making the extract an excellent candidate for drug development. The ethnopharmacological use of A. occidentale by populations for the treatment of DIP’s and neurodegenerative diseases, reveal that this organ has biological actions against microorganisms that cause infections, as well as being capable of causing toxicity in cancer cells.

This study aimed to evaluate the antibacterial activity and to verify, in silico and in vitro, the inhibition of efflux mechanisms using a series of synthesized 1,8-naphthyridines sulfonamides against Staphylococcus aureus strains carrying MepA efflux pumps. The chemical synthesis occurred through the thermolysis of the Meldrum's acid adduct. The sulfonamide derivatives were obtained by the sulfonylation of 2-amino-5‑chloro-1,8-naphthyridine with commercial benzenesulfonyl chloride. Antibacterial activity was assessed by the broth microdilution test. Efflux pump inhibitory capacity was evaluated in silico by molecular docking and in vitro by analyzing synergistic effects on ciprofloxacin and ethidium bromide (EtBr) and by EtBr fluorescence emission assays. The following 1,8-naphthyridines were synthesized: 4-methyl-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10a); 2,5-dichloro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10b); 4-fluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10c); 2,3,4-trifluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10d); 3-trifluoromethyl-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10e); 4‑bromo-2,5-difluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10f). The 1,8-naphthyridines derivatives associated with sulfonamides did not show antibacterial activity. However, they showed a favorable pharmacokinetic profile with possible MepA efflux pump inhibitory action, demonstrated in molecular docking. In addition to the promising results in reducing the concentration of intracellular EtBr. 1,8-naphthyridines act as putative agents in the inhibitory action of the MepA efflux pump.

Staphylococcus aureus is a Gram-positive bacterium responsible for a number of diseases and has demonstrated resistance to conventional antibiotics. This study aimed to evaluate the antibacterial activity of eugenol and its derivatives allylbenzene, 4-allylanisole, isoeugenol and 4-allyl-2,6-dimethoxyphenol against the S. aureus NorA efflux pump (EP) in association with norfloxacin and ethidium bromide. The antibacterial activity of the compounds was assessed using the broth microdilution method to determine the minimum inhibitory concentration (MIC). A reduction in the MIC of ethidium bromide (a substrate for several efflux pumps) or norfloxacin was used as a parameter of EP inhibition. Molecular modeling studies were used to predict the 3D structure and analyze the interaction of selected compounds with the binding pocket of the NorA efflux pump. Except for 4-allylanisole and allylbenzene, the compounds presented clinically effective antibacterial activity. When associated with norfloxacin against the SA 1199B strain, 4-allyl-2,6-dimethoxyphenol eugenol and isoeugenol caused significant reduction in the MIC of the antibiotic, demonstrating synergistic effects. Similar effects were observed when 4-allyl-2,6-dimethoxyphenol, allylbenzene and isoeugenol were associated with ethidium bromide. Together, these findings indicate a potential inhibition of the NorA pump by eugenol and its derivatives. This in vitro evidence was corroborated by docking results demonstrating favorable interactions between 4-allyl-2,6-dimetoxypheno and the NorA pump mediated by hydrogen bonds and hydrophobic interactions. In conclusion, eugenol derivatives have the potential to be used in antibacterial drug development in strains carrying the NorA efflux pump.

Naphthyridines represent a class of heterocyclic compounds formed by two condensed aromatic rings. This study aimed to evaluate the antibacterial activity and in vitro inhibition of efflux resistance mechanisms of a series of 1,8-naphthyridine sulfonamides against strains carrying Tet(K) and MsrA efflux pumps. The efflux pump inhibitory capacity was evaluated by analyzing synergistic effects between 1,8-naphthyridine sulfonamides and standard antibiotics, as well as ethidium bromide. The following 1,8-naphthyridines were used: 4-methyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Naph 1); 2,5-Dichloro-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Naph 2); 2,3,4-trifluoro-N-(5-chloro-1,8-naphthyridin-2-yl)benzenesulfonamide (Naph 7); 3-trifluoromethyl-N-(5-chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Naph 9). The 1,8-naphthyridine sulfonamide derivatives possessed a potential Tet(K) and MsrA efflux pump inhibitory action.

Chrysobalanus icaco L. is a native plant of Brazil used as a food source and traditionally for the treatment of various diseases. The aim of study was performed the phytochemical analysis by UPLC-DAD-ESI-QTOF-MS/MS, and evaluated acute and repeated dose oral toxicities of the C. icaco L. leaf aqueous extract (AECi). The acute toxicity study was performed using a dose of AECi 2000 mg/kg, while the repeated dose toxicity study, the AECi was administered daily at doses of 100, 200 and 400 mg/kg, for 28 days. Behavior and mortality of animals were observed during the test period and body weight, as well water and eating consumption. Hematological, biochemical parameters and histopathological examinations were carried out. Phytochemical analysis of the AECi revealed the presence of flavonoids and tannins. Oral single dose of 2000 mg/kg of AECi resulted in no mortalities or abnormal clinical signs. Studies of repeated dose toxicity promoted a reduction in the body weight of treated animals and an increase of hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in both, males and females. Histopathological analyzes showed alterations in the livers of animals treated with AECi. Thus, this study recommends the population take care when using this species, especially during prolonged periods.