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BACKGROUND: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. OBJECTIVES: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. METHODS: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. RESULTS: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action. CONCLUSIONS: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.
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Anti-Infecciosos , Tiadiazinas , Antibacterianos/farmacologia , Tiadiazinas/farmacologia , Tiadiazinas/química , Norfloxacino/farmacologia , Anti-Inflamatórios , Testes de Sensibilidade MicrobianaRESUMO
Efflux pumps are proteins capable of expelling antibiotics from bacterial cells, have emerged as a major mechanism of bacterial resistance. In the ongoing pursuit to overcome and reduce bacterial resistance, novel substances are being explored as potential efflux pump inhibitors. Meldrum's acid, a synthetic molecule widely studied for its role in synthesizing bioactive compounds, holds promise in this regard. Therefore, the objective of this study is to evaluate the antibacterial activity of three derivatives of Meldrum's acid and assess their ability to inhibit efflux mechanisms, employing both in silico and in vitro approaches. The antibacterial activity of the derivatives was assessed using a broth microdilution testing method. Surprisingly, the derivatives did not exhibit direct antibacterial activity on their own. However, they displayed a significant effect in enhancing the efficacy of antibiotics, suggesting a potential role in potentiating their effects. Furthermore, fluorescence emission assays using ethidium bromide indicated that the derivatives could potentially block efflux pumps, as they exhibited fluorescence levels comparable to the positive control. To further investigate their inhibitory capacity, molecular docking studies were conducted in silico, revealing binding interactions similar to ciprofloxacin and carbonyl cyanide 3-chlorophenylhydrazone, known efflux pump inhibitors. These findings highlight the potential of Meldrum's acid derivatives as effective inhibitors of efflux pumps. By targeting these mechanisms, the derivatives offer a promising avenue to enhance the effectiveness of antibiotics and combat bacterial resistance. This study underscores the importance of exploring novel strategies in the fight against bacterial resistance and provides valuable insights into the potential of Meldrum's acid derivatives as efflux pump inhibitors. Further research and exploration in this field are warranted to fully exploit their therapeutic potential.
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Antibacterianos , Proteínas de Bactérias , Simulação de Acoplamento Molecular , Proteínas de Bactérias/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química , Dioxanos , Testes de Sensibilidade MicrobianaRESUMO
Multidrug resistance is a significant health problem worldwide, with increasing mortality rates, especially in the last few years. In this context, a consistent effort has been made to discover new antibacterial agents, and evidence points to natural products as the most promising source of bioactive compounds. This research aimed to characterize the antibacterial effect of the essential oil of Etlingera elatior (EOEE) and its major constituents against efflux pump-carrying Staphylococcus aureus strains. The essential oil was extracted from fresh inflorescences by hydrodistillation. Chemical analysis was performed using gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography equipped with a flame ionization detector (GC-FID). The strains RN-4220, 1199B, IS-58, and 1199 of S. aureus were used to evaluate the antibacterial activity and the inhibition of efflux pumps. A total of 23 compounds were identified, including dodecanal and 1-dodecanol as major compounds. EOEE and dodecanal showed weak activity against the strains, while 1-dodecanol inhibited bacterial growth at low concentrations, indicating strong antibacterial activity. In addition, this compound potentiated the activity of norfloxacin against S. aureus 1199. In conclusion, 1-dodecanol was identified as the most effective compound of EOEE, showing significant potential to be used in antibacterial drug development.
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Óleos Voláteis , Staphylococcus aureus , Cromatografia Gasosa-Espectrometria de Massas , Antibacterianos/farmacologia , Antibacterianos/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Dodecanol/farmacologiaRESUMO
Ziziphus joazeiro Mart. is an endemic plant of the Caatinga that presents a great socioeconomic importance for the Northeast and Semiarid Region of Brazil. In view of this, this study aimed to evaluate the antibacterial activity and anxiolytic-like effects of Ziziphus joazeiro Mart leaves in adult zebrafish (Danio rerio). The characterization of the main classes of metabolites was performed through chemical reactions. The antibacterial and antibiotic potentiating activity was evaluated by broth microdilution assays. The 96 h acute toxicity, open field test and anxiety models test was evaluated in vivo on adult zebrafish. The results obtained in the phytochemical prospection evidenced the presence of flobabenic tannins, leucoanthocyanidins, flavonois, flavonones, catechins, alkaloids, steroids, and triterpenoids. EEFZJ did not show antibacterial activity for all microorganism tested (MIC ≥ 1024 µg/mL), but reduced the concentration required for bacterial growth inhibition in combination with gentamicin and norfloxacin against multidrug-resistant strains of S. aureus (SA10) and E. coli (EC06), exhibiting synergistic effect with these antibiotics (p<0.0001). In the tests in vivo, EEFZJ was found to be nontoxic, performing reduced locomotor activity and demonstrated an anxiolytic-like effect in adult zebrafish via GABAergic and Serotoninergic systems (5-HT1, 5-HT2A/2C and 5-HT3A/3B).
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Antimicrobial resistance has become a growing public health concern in recent decades, demanding a search for new effective treatments. Therefore, this study aimed to elucidate the phytochemical composition and evaluate the antibacterial activity of the essential oil obtained from the fruits of Piper tuberculatum Jacq. (EOPT) against strains carrying different mechanisms of antibiotic resistance. Phytochemical analysis was performed using gas chromatography-mass spectrometry (GC/MS). The antibacterial activity of EOPT and its ability to inhibit antibiotic resistance was evaluated through the broth microdilution method. The GC-MS analysis identified 99.59% of the constituents, with ß-pinene (31.51%), α-pinene (28.38%), and ß-cis-ocimene (20.22%) being identified as major constituents. The minimum inhibitory concentration (MIC) of EOPT was determined to assess its antibacterial activity against multidrug-resistant strains of Staphylococcus aureus (IS-58, 1199B, K2068, and K4100). The compound showed a MIC of ≥ 1024 µg/mL, suggesting a lack of intrinsic antibacterial activity. However, when the EOPT was associated with antibiotics and EtBr, a significant decrease in antibiotic resistance was observed, indicating the modulation of efflux pump activity. This evidence was corroborated with the observation of increased fluorescent light emission by the bacterial strains, indicating the involvement of the NorA and MepA efflux pumps. Additionally, the significant potentiation of ampicillin activity against the S. aureus strain K4414 suggests the ß-lactamase inhibitory activity of EOPT. These results suggest that the essential oil from P. tuberculatum fruits has antibiotic-enhancing properties, with a mechanism involving the inhibition of efflux pumps and ß-lactamase in MDR S. aureus strains. These findings provide new perspectives on the potential use of EOPT against antibiotic resistance and highlight the importance of Piper species as sources of bioactive compounds with promising therapeutic activities against MDR bacteria. Nevertheless, further preclinical (in vivo) studies remain necessary to confirm these in vitro-observed results.
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Artocarpus heterophyllus (jackfruit) is an evergreen tree distributed in tropical regions and is among the most studied species of the genus Artocarpus. The jackfruit almond has been highlighted in relation to phytochemical studies, biological properties, and application in the development of food products. This study aimed to analyze jackfruit fixed oil regarding chemical components, antibacterial property alone, and in association with antibiotics against standard and MDR bacteria strains. In the analysis of the oil by gas chromatography coupled to a flame ionization detector (GC-FID), a high content of saturated fatty acids (78.51%) was identified in relation to unsaturated fatty acids (17.07%). The main fatty acids identified were lauric acid (43.01%), myristic acid (11.10%), palmitic acid (6.95%), and oleic acid (15.32%). In the antibacterial analysis, broth microdilution assays were used. The oil presented minimum inhibitory concentration (MIC) ≥ 1024 µg/mL in antibacterial analysis for standard and MDR bacterial strains. The oil showed synergistic effects in the association with gentamicin, ofloxacin, and penicillin against MDR strains, with significant reductions in the MIC of antibiotics. The results suggest that the fixed oil of A. heterophyllus has fatty acids with the potential to synergistically modify antibiotic activity.
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Yeasts from the Candida parapsilosis complex are clinically relevant due to their high virulence and pathogenicity potential, such as adherence to epithelial cells and emission of filamentous structures, as well as their low susceptibility to antifungals. D-limonene, a natural compound, emerges as a promising alternative with previously described antibacterial, antiparasitic, and antifungal activity; however, its mechanisms of action and antivirulence activity against C. parapsilosis complex species have not been elucidated. Therefore, in the present study, we aimed to evaluate the antifungal and antivirulence action, as well as the mechanism of action of D-limonene against isolates from this complex. D-limonene exhibited relevant antifungal activity against C. parapsilosis complex yeasts, as well as excellent antivirulence activity by inhibiting yeast morphogenesis and adherence to the human epithelium. Furthermore, the apoptotic mechanism induced by this compound, which is not induced by oxidative stress, represents an important target for the development of new antifungal drugs.
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Antifúngicos , Candida parapsilosis , Humanos , Antifúngicos/farmacologia , Virulência , Limoneno/farmacologia , Fatores de Virulência , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiaeRESUMO
The inappropriate use of synthetic antibiotics has become a global public health problem. Therefore, the study of new alternatives for the treatment of infectious diseases is relevant and natural bioactive products are on the rise. This study conducted a scientific prospection of bioactive natural products with promising applications in the chemical control of microorganisms. A systematic review of the most recent articles was performed according to the following three steps: (i) eligibility assessment, (ii) screening, and (iii) inclusion of articles and information extraction. There has been an increase in the number of scientific publications on bioactive natural products for microbial control in the CAPES and SciELO databases (2001-2021). Seventeen relevant articles were included, most of which focused on extracts. Ascorbic acid, chlorogenic acid, chrysin, and quercetin were the most cited compounds. Natural products were shown to be effective in inhibiting more than 30 microorganisms. A discussion was presented on the research trends.
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Produtos Biológicos , Antibacterianos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ácido Clorogênico , Extratos Vegetais/química , QuercetinaRESUMO
Caffeic acid is a phenolic compound widely found in commonly consumed foods such as pears, apples and coffee, and is pharmacologically known for its antioxidant, anti-inflammatory and anti-asthmatic properties. However, its relaxant activity in the aorta, uterus and ileum smooth muscle has not been investigated. This study aimed to comparatively evaluate the effect of caffeic acid on smooth muscle from different organs (aorta, uterus and ileum), and the contractions of this different organ were induced by different agonists. The organ bath technique was used, where the organs were placed in different cuvettes with 10 mL of Tyrode solution for 1 h to stabilize, then, myometrial, intestinal strip and aortic ring contractions were evoked using different contractile agonists (KCl 60 mM, PHE 0.1 µM, OT 10-2 IU/mL, CCh 10-6 M and BaCl2 0.1-30 mM); increasing concentrations of caffeic acid (0.03-7 mM) were administered in the experimental preparations. In the presence of KCl (60 mM), caffeic acid caused relaxations with the following EC50 values: 2.7 ± 0.26 mM/mL (aorta), 5.7 ± 0.71 mM/mL (uterus) and 2.1 ± 0.39 mM/mL (ileum). When in the presence of different agonists, PHE (0.1 µM) for the aorta, OT (10-2 IU/mL) for the uterus and CCh (10-6 M) for the ileum, caffeic acid caused relaxations with EC50 values of: 2.7 ± 0.31 mM/mL; 2.2 ± 0.34 mM/mL and 2.0 ± 0.28 mM/mL, respectively. The inhibitory effect of caffeic acid on serotonergic (aorta and uterus) and muscarinic receptors (uterus and ileum), as well as its possible involvement with L-type Ca2+ channels, was also observed. This study reports the pharmacological characterization of caffeic acid on smooth muscle from different organs, for which caffeic acid was more potent in the ileum. A diverse understanding of its performance as a possible therapeutic product is attributed to its relaxant effect.
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Aorta/fisiologia , Ácidos Cafeicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Íleo/fisiologia , Músculo Liso/fisiologia , Fenóis/farmacologia , Útero/fisiologia , Animais , Aorta/efeitos dos fármacos , Ácidos Cafeicos/química , Canais de Cálcio Tipo L/metabolismo , Carbacol/farmacologia , Feminino , Íleo/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ocitocina/farmacologia , Fenóis/química , Fenilefrina/farmacologia , Cloreto de Potássio , Ratos Wistar , Útero/efeitos dos fármacosRESUMO
Introduction: Farnesol (C15H26O) is a sesquiterpene alcohol found in essential oils. This substance is reported to have different pharmacological activities such as antimicrobial, antitumor and antioxidant effects, as well as actions in different body systems.Areas covered: This study aimed to analyze pharmaceutical patents containing this substance in their formulations. Patent search was carried out through the WIPO (World Intellectual Property Organization), LatiPat and INPI (National Institute of Industrial Property) electronic banks using the following descriptors and combinations: 'farnesol', 'pharmaceutical product', 'pharmacology' and 'pharmacy'.Expert opinion: Primary research identified 54 patents, from which 17 were selected for the final analysis after applying the inclusion criteria. The selected patents referred to products presenting different pharmaceutical activities of interest such as the prevention and treatment of diseases affecting the dermis, central nervous and cardiovascular systems, diseases caused by different microorganisms and cancers, among others. A minority of the articles included in this review reported the type of farnesol isomer that was investigated, this becoming a major limitation for the development of future pharmaceutical products. With the completion of this study, farnesol presents itself as a potential agent with pharmacological application both in the prevention and treatment of different diseases.