RESUMO
Nitroimidazole compounds are well-known bioactive substances, and the structural activity relationship has been reported whereby the position of the nitro group within the imidazole ring has a large influence on the activity. This study focuses on synthesising new trypanocidal agents from the hybridisation of metronidazole with different natural phenols (eugenol, dihydroeugenol and guaiacol). Two different coupling methodologies have been explored in order to analyse the influence of the connector on bioactivity: i) classic direct esterification (AD compounds) and ii) "click" chemistry using a triazole connector (AC compounds). The in vitro trypanocidal tests show good results for both AC and AD hybrid compounds against both epimastigote and trypomastigote forms of T. cruzi. In silico studies showed positive data for most of the synthesised compounds and, in general present low toxicological risks. The AC compounds present lower ClogP (lipophilicity) values than those found for the AD series and higher TPSA (topological polar surface area) values, suggesting lower lipophilicity may be related to the presence of the triazole connector. The AD series compounds have higher Drug Score values than the AC series derivatives, suggesting better general properties for a pharmacological action.
Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Humanos , Doença de Chagas/tratamento farmacológico , Eugenol , Metronidazol/farmacologia , Metronidazol/uso terapêutico , Relação Estrutura-Atividade , Triazóis/uso terapêutico , Tripanossomicidas/química , Guaiacol/síntese química , Guaiacol/química , Guaiacol/farmacologiaRESUMO
Historically, the piperazine moiety has been demonstrated to possess pharmacophoric properties, and has subsequently been incorporated in many drugs that have antitumor, antimalarial, antiviral, antibacterial and antifungal properties. Derivatives of eugenol and dihydroeugenol have also been reported as being bioactive compounds. This study reports the synthesis of a range of eugenol/dihydroeugenol - piperazine derivatives which have been tested as antimicrobial compounds against Gram positive, Gram negative and rapid-growing mycobacteria (RGM). The rationale employed in the design of the structural pattern of these new derivatives, provides useful insights into the structure-activity relationships (SAR) of the series. Antimicrobial activity tests were extremely encouraging, with the majority of the synthesised compounds being more active than eugenol and dihydroeugenol starting materials. The antimicrobial potential was most notable against the Gram-negative species K. pneumoniae and P. aeruginosa, but there was also significant performance against the Gram-positive strains S. epidermidis and S. aureus and the Rapidly Growing Mycobacteria (RGM) strains tested. Tests using the synthesised compounds against multidrug-resistance clinical (MDR) isolates also showed high activity. The biofilm inhibition tests using M. fortuitum showed that all evaluated derivatives were able to inhibit biofilm formation even at low concentrations. In terms of structural-activity relationships; the results generated by this study demonstrate that the compounds with bulky substituents on the piperazine subunit were much more active than those with less bulky groups, or no groups. Importantly, the derivatives with a sulfonamide side chain were the most potent compounds. A further observation was that those compounds with a para-substituted benzenesulfonamide ring stand out, regardless of whether this substituent is a donor or an electron-withdrawing group.
Assuntos
Anti-Infecciosos , Eugenol , Eugenol/farmacologia , Piperazina/farmacologia , Staphylococcus aureus , Testes de Sensibilidade Microbiana , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Micobactérias não TuberculosasRESUMO
Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 Mpro with IC50 values of 0.4-3 µM. They were also shown to inhibit SARS-CoV-1 Mpro and human cathepsin L. Molecular dynamics simulations indicated the stability of the Mpro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 Mpro inhibitors.
Assuntos
COVID-19 , Tiossemicarbazonas , Humanos , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/química , Tiossemicarbazonas/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Proteínas não Estruturais ViraisRESUMO
This work describes the design, synthesis and antifungal activity of new imidazoles and 1,2,4-triazoles derived from eugenol and dihydroeugenol. These new compounds were fully characterized by spectroscopy/spectrometric analyses and the imidazoles 9, 10, 13 e 14 showed relevant antifungal activity against Candida sp. and Cryptococcus gattii in the range of 4.6-75.3 µM. Although no compound has shown a broad spectrum of antifungal activity against all evaluated strains, some azoles were more active than either reference drugs employed against specific strains. Eugenol-imidazole 13 was the most promising azole (MIC: 4.6 µM) against Candida albicans being 32 times more potent than miconazole (MIC: 150.2 µM) with no relevant cytotoxicity (selectivity index >28). Notably, dihydroeugenol-imidazole 14 was twice as potent (MIC: 36.4 µM) as miconazole (MIC: 74.9 µM) and more than 5 times more active than fluconazole (MIC: 209.0 µM) against alarming multi-resistant Candida auris. Furthermore, in vitro assays showed that most active compounds 10 and 13 altered the fungal ergosterol biosynthesis, reducing its content as fluconazole does, suggesting the enzyme lanosterol 14α-demethylase (CYP51) as a possible target for these new compounds. Docking studies with CYP51 revealed an interaction between the imidazole ring of the active substances with the heme group, as well as insertion of the chlorinated ring into a hydrophobic cavity at the binding site, consistent with the behavior observed with control drugs miconazole and fluconazole. The increase of azoles-resistant isolates of Candida species and the impact that C. auris has had on hospitals around the world reinforces the importance of discovery of azoles 9, 10, 13 e 14 as new bioactive compounds for further chemical optimization to afford new clinically antifungal agents.
Assuntos
Antifúngicos , Cryptococcus gattii , Antifúngicos/farmacologia , Antifúngicos/química , Azóis/farmacologia , Azóis/química , Miconazol/farmacologia , Candida , Fluconazol , Eugenol/farmacologia , Eugenol/química , Testes de Sensibilidade Microbiana , Candida albicans , Imidazóis/farmacologia , ErgosterolRESUMO
The problem of antibiotic resistance by bacteria threatens human health. Therefore, studies in this area seek alternatives to circumvent it. The study with coumarins and eugenol has already proven that these classes of compounds act against bacteria. In this same aspect, exposure to LED also shows a bactericidal effect. Seeking a possible enhancement of this effect, the present work studied coumarins derived from eugenol in association with LED to investigate the bactericidal effect. Four compounds were tested. For this, minimum inhibitory concentrations (MICs) and modulation with three antibiotics against Escherichia coli and Staphylococcus aureus bacteria were determined. To test the behavior of the activity against exposure to LED, the plates were exposed for 20 min to blue light, 415 nm and then incubated at 37°C for 24 h. For control, duplicates were made, and one of them did not undergo this exposure. C1 exhibited better activity against S. aureus, as synergism prevailed under the conditions tested. C3 and C4 were promising against E. coli as they showed synergism in association with the three antibiotics both with and without LED exposure. Thus, the compounds showed bactericidal activity, and LED was shown to enhance synergism.
Assuntos
Eugenol , Staphylococcus aureus , Humanos , Eugenol/farmacologia , Escherichia coli , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Cumarínicos/farmacologiaRESUMO
A series of structural analogs of aryl sulfonamide hybrid compounds were synthesised and their cytotoxic activity was evaluated against three human breast cancer cell lines (MCF-7, MDA-MB-231 and Hs 578T). The compounds were designed through electronic, hydrophobic and steric modifications using the chemical structure of N-{4-[(2-hydroxy-3-methoxy-5-propylphenyl)sulfamoyl]phenyl}acetamide (referred to as compound 7) as a starting point to then assess a structure-activity relationship (SAR) study. From the data generated, we observed that compounds 9, 10 and 11 (which have modifications in the substituents of the aryl sulfonamide), efficiently reduced the cell viability of MCF-7 and MDA-MB-231 cell cultures. Based on initial data, we selected compounds 10 and 11 for further investigations into their antiproliferative and/or cytotoxic profile against MDA-MB-231 cells, and we noted that compound 10 was the most promising compound in the series. Compound 10 promoted morphological changes and altered the dynamics of cell cycle progression in MDA-MB-231 cells, inducing arrest in G1/S transition. Taken together, these results show that the dihydroeugenol-aryl-sulfonamide hybrid compound 10 (which has an electron withdrawing nitro group) displays promising antiproliferative activity against MDA-MB-231 cell lines.
Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Sulfonamidas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células , Relação Estrutura-Atividade , Antineoplásicos/química , Linhagem Celular , Linhagem Celular Tumoral , Apoptose , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Background: Eugenol shows both antibacterial and antiparasitic activities, suggesting that it might be evaluated as an option for the treatment of praziquantel-resistant schistosome. Methods: The in vitro activities of three eugenol derivatives (FB1, FB4 and FB9) on adult worms from Schistosoma mansoni were examined by fluorescence and scanning electron microscopy to analyze effects on the excretory system and integument damage, respectively. Biochemical tests with verapamil (a calcium channel antagonist) and ouabain (a Na+/K+-ATPase pump inhibitor) were used to characterize eugenol derivative interactions with calcium channels and the Na+/K+-ATPase, while in silico analysis identified potential Na+/K+-ATPase binding sites. Results: The compounds showed effective doses (ED50) of 0.324 mM (FB1), 0.167 mM (FB4), and 0.340 mM (FB9). In addition, FB4 (0.322 mM), which showed the lowest ED50, ED90 and ED100 (p < 0.05), caused the most damage to the excretory system and integument, according to both fluorescence and scanning electron microscopy analysis. The death of adult worms was delayed by ouabain treatment plus FB1 (192 versus 72 hours) and FB9 (192 versus 168 hours), but the response to FB4 was the same in the presence or absence of ouabain. Besides, no changes were noted when all of the eugenol derivatives were combined with verapamil. Moreover, FB1 and FB9 inhibited Na+/K+-ATPase activity according to in silico analysis but FB4 did not show a time-dependent relationship and may act on targets other than the parasite Na+/K+-ATPase. Conclusion: Eugenol derivatives, mainly FB4 when compared to FB1 and FB9, seem to act more effectively on the integument of adult S. mansoni worms.
RESUMO
We report here a series of glucosides which are active as inhibitors of the angiotensin converting enzyme (ACE). They are structurally related to the natural compound eugenol and exhibited significant inhibition values. Their syntheses were expeditious and we could obtain informative docking plots of them complexed to this enzyme. A glucoside derived from eugenol, carrying a carboxylic group in the aglycone, was the most active of them (with an IC50 of 0.4 mM) and showed good binding energies in docking studies with ACE. Moreover, computational prediction of toxicity risks, physicochemical properties and drug score show that the glucoside derivative of eugenol is a suitable compound for optimisation studies aimed at finding new drug candidates.
Assuntos
Eugenol , Peptidil Dipeptidase A , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Eugenol/farmacologia , Glucosídeos/química , Glucosídeos/farmacologia , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismoRESUMO
Background Eugenol shows both antibacterial and antiparasitic activities, suggesting that it might be evaluated as an option for the treatment of praziquantel-resistant schistosome. Methods The in vitro activities of three eugenol derivatives (FB1, FB4 and FB9) on adult worms from Schistosoma mansoni were examined by fluorescence and scanning electron microscopy to analyze effects on the excretory system and integument damage, respectively. Biochemical tests with verapamil (a calcium channel antagonist) and ouabain (a Na+/K+-ATPase pump inhibitor) were used to characterize eugenol derivative interactions with calcium channels and the Na+/K+-ATPase, while in silico analysis identified potential Na+/K+-ATPase binding sites. Results The compounds showed effective doses (ED50) of 0.324 mM (FB1), 0.167 mM (FB4), and 0.340 mM (FB9). In addition, FB4 (0.322 mM), which showed the lowest ED50, ED90 and ED100 (p < 0.05), caused the most damage to the excretory system and integument, according to both fluorescence and scanning electron microscopy analysis. The death of adult worms was delayed by ouabain treatment plus FB1 (192 versus 72 hours) and FB9 (192 versus 168 hours), but the response to FB4 was the same in the presence or absence of ouabain. Besides, no changes were noted when all of the eugenol derivatives were combined with verapamil. Moreover, FB1 and FB9 inhibited Na+/K+-ATPase activity according to in silico analysis but FB4 did not show a time-dependent relationship and may act on targets other than the parasite Na+/K+-ATPase. Conclusion Eugenol derivatives, mainly FB4 when compared to FB1 and FB9, seem to act more effectively on the integument of adult S. mansoni worms.(AU)
Assuntos
Schistosoma/efeitos dos fármacos , Esquistossomose/tratamento farmacológico , Esquistossomicidas/análise , Técnicas In Vitro , Simulação por Computador , Eugenol/análogos & derivados , Doenças Negligenciadas/tratamento farmacológicoRESUMO
This work describes the synthesis, anti-Candida, and molecular modeling studies of eighteen new glucosyl-1,2,3-triazoles derived from eugenol and correlated phenols. The new compounds were characterized by combined Fourier Transform Infrared, 1 H and 13 C nuclear magnetic resonance and spectroscopy of high-resolution mass spectrometry. The synthesized compounds did not show significant cytotoxicity against healthy fibroblast human cells (MCR-5) providing interesting selectivity indexes (SI) to active compounds. Considering the antifungal activity, nine compounds showed anti-Candida potential and the peracetylated triazoles 17 and 18 were the most promising ones. Eugenol derivative 17 was active against three species of Candida at 26.1-52.1 µM. This compound was four times more potent than fluconazole against Candida krusei and less toxic (SI > 6.6) against the MCR-5 cells than fluconazole (SI > 3.3) considering this strain. Dihydroeugenol derivative 18 showed similar activity to 17 and was four times more potent and less toxic than fluconazole against C. krusei. The deacetylated glucosides and non-glucosylated corresponding derivatives did not show considerable antifungal action, suggesting that the acetyl groups are essential for their anti-Candida activity. Molecular docking coupled with molecular dynamics showed that 14α-lanosterol demethylase is a feasible molecular target, since 17 and 18 could bind to this enzyme once deacetylated in vivo, thereby acting as prodrugs. Also, these studies demonstrated the importance of hydrophobic substituents at the phenyl ring.
Assuntos
Antifúngicos/síntese química , Eugenol/química , Triazóis/síntese química , Antifúngicos/farmacologia , Apoptose/efeitos dos fármacos , Candida/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/citologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
BACKGROUND: The search for new drug compounds is always challenging and there are several different strategies that involve the most varied and creative approaches in medicinal chemistry. One of them is the technique of molecular hybridisation: forming a hybrid compound from two or more pharmacophoric subunits. These hybrids may maintain the characteristics of the original compound and preferably show improvements to its pharmacological action, with reduced side effects and lower toxicity when compared to the original components. This study specifically focuses on synthesising hybrid molecules which demonstrate trypanocidal activity against the epimastigote and trypomastigote forms of Trypanosoma cruzi. METHODS: In this context, this study centres on the synthesis of a novel structural scaffold via molecular hybridisation; by using a triazole species to link a metronidazole unit to a eugenol analogue unit, the objective being to combine their therapeutic properties into a new molecular structure. The resulting hybrid molecules were evaluated against T. cruzi which is responsible for high incidences of trypanosomiasis in tropical countries such as Brazil. RESULTS: The results of this study showed an improvement in the anti-parasitic activity of the hybrid compounds with the best result coming from hybrid compounds [8] and [9], which present an activity similar to the control drug benznidazole. The new compounds, utilising a triazole species as a coupling connector, demonstrated promising results and has highlighted the path for planning similar structural patterns to investigate new compounds. CONCLUSIONS: In summary, we can conclude that the synthesised hybrid compounds demonstrate that using a triazole to link metronidazole with natural phenols, produces hybrid molecules that are promising as a new class of compounds of therapeutic interest for further investigation.
Assuntos
Eugenol/farmacologia , Metronidazol/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Eugenol/síntese química , Eugenol/química , Metronidazol/síntese química , Metronidazol/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/químicaRESUMO
Changes in host immunity and parasite resistance to drugs are among the factors that contribute to decreased efficacy of antiparasitic drugs such as the antimonial compounds pentamidine, amphotericin (AMP B) and miltefosine. Bioactive natural products could be alternatives for the development of new drugs to treat neglected human diseases such as leishmaniasis. Natural coumarins and synthetic analogues have shown leishmanicidal activity, mainly in vitro. This study investigated the in vitro and in vivo leishmanicidal activity of synthetic coumarin compounds (C1-C5) in parasites Leishmania (L.) amazonensis and L. (L.) infantum chagasi. The cytotoxicity of these compounds in mammalian cells and their influence on production of reactive oxygen species was also investigated. In vitro assays showed that 8-methoxy-3-(4-nitrobenzoyl)-6-propyl-2H-chromen-2-one (C4) was as active as AMP B mainly in the amastigote form (p < 0.05); C4 presented a selectivity index (65.43) four times higher than C2 (15.4) in L. amazonensis and six times higher (33.94) than C1 (5.46) in L. infantum chagasi. Additionally, coumarin C4 reduced the H2O2 concentration 32.5% more than the control group in L. amazonensis promastigotes during the lag phase of proliferation. No interference of C4 was observed on the mitochondrial membrane potential of the parasites. In vivo, coumarin C4 in corn oil (oral route) led to a reduction in the number of amastigotes from L. infantum chagasi to 1.31 × 106 and 4.09 × 104 in the spleen and liver, respectively (p < 0.05). Thus, C4 represents a candidate for further studies aiming at new treatments of leishmaniasis.
Assuntos
Antiprotozoários/farmacologia , Cumarínicos/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/prevenção & controle , Administração Oral , Anfotericina B/administração & dosagem , Anfotericina B/química , Anfotericina B/farmacologia , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Cumarínicos/administração & dosagem , Cumarínicos/química , Cricetinae , Feminino , Interações Hospedeiro-Parasita/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Leishmania/classificação , Leishmania/fisiologia , Leishmaniose/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mesocricetus , Estrutura Molecular , Especificidade da EspécieRESUMO
Sulfonamides have been in clinical use for many years, and the development of bioactive substances containing the sulfonamide subunit has grown steadily in view of their important biological properties such as antibacterial, antifungal, antiparasitic, antioxidant, and antitumour properties. This review addresses the medicinal chemistry aspects of sulfonamides; covering their discovery, the structure- activity relationship and the mechanism of action of the antibacterial sulfonamide class, as well as the physico-chemical and pharmacological properties associated with this class. It also provides an overview of the various biological activities inherent to sulfonamides, reporting research that emphasises the importance of this group in the planning and development of bioactive substances, with a special focus on potential antitumour properties. The synthesis of sulfonamides is considered to be simple and provides a diversity of derivatives from a wide variety of amines and sulfonyl chlorides. The sulfonamide group is a non-classical bioisostere of carboxyl groups, phenolic hydroxyl groups and amide groups. This review highlights that most of the bioactive substances have the sulfonamide group, or a related group such as sulfonylurea, in an orientation towards other functional groups. This structural characteristic was observed in molecules with distinct antibacterial activities, demonstrating a clear structure-activity relationship of sulfonamides. This short review sought to contextualise the discovery of classic antibacterial sulfonamides and their physico-chemical and pharmacological properties. The importance of the sulfonamide subunit in Medicinal Chemistry has been highlighted and emphasised, in order to promote its inclusion in the planning and synthesis of future drugs.
Assuntos
Antibacterianos/química , Antineoplásicos/química , Sulfonamidas/química , Actinobacillus/efeitos dos fármacos , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Tetra-Hidrofolato Desidrogenase/química , Tetra-Hidrofolato Desidrogenase/metabolismoRESUMO
Coumarins are widely distributed substances in plant species that promote phytotoxic effects, allowing them to be exploited as herbicides less harmful to the environment, since many invasive species have demonstrated resistance to commercially available products. The derived coumarins used in this study had not been tested in plant models and their effect on plants was unknown. The objective of this study was to evaluate the phytotoxic action of these coumarins in bioassays with Lactuca sativa L., in order to select the most responsive substance whose toxicity was best elucidated by chromosomal complement and enzymatic antioxidant metabolism studies. From the phytotoxicity assays, coumarin 8-methoxy-2-oxo-6-(prop-2-en-1-yl)-2H-chromene-3-carboxylic acid (A1), reported here for the first time, was selected as the most responsive and caused a reduction in the following parameters: number of normal seedlings, fresh biomass, root length and shoot length. Subsequent studies demonstrated that this coumarin is cytogenotoxic due to damage caused to the cell cycle and the occurrence of chromosomal abnormalities. However, it did not interfere with antioxidant enzyme activity and did not cause lipid peroxidation. The changes caused by coumarin A1 described herein can contribute to better understanding the allelochemical actions of coumarins and the potential use of these substances in the production of natural herbicides.
RESUMO
Several species of rapidly growing mycobacteria (RGM) have been associated with biofilms in areas such as biomedical devices, water distribution systems, cosmetic surgery, and catheter-related blood infections. Biofilms which exhibit antimicrobial resistance such as those formed by the genus Mycobacterium pose a significant risk to health and are of particular interest to researchers. Licarin A (a neolignan found in numerous plant species e.g. nutmeg) has been reported to show a wide range of biological actions including anti-inflammatory, antioxidant, and antibacterial properties. The aim of this study was to prepare a set of Licarin A derivatives and investigate the impact of specific structural changes on its antimycobacterial ability, and its effect on the biofilm formation of RGM species. Initially, the phenolic sub-unit and alkenyl side chain of Licarin A were modified to create derivatives with a higher partition coefficient; as the activity of a compound against mycobacteria seems to be strongly influenced by its hydrophobicity. Further, polar groups were inserted into the side chain to change the hydrophilic-lipophilic profile of the molecules. Results showed variability in the susceptibility profile of mycobacteria against the Licarin A derivatives under analysis. A number of the derivatives showed significant inhibitory activity of planktonic growth of the three strains of mycobacteria used, with even lower MIC values than those observed with reference drugs and Licarin A itself. Cytotoxicity assays showed they also have low toxicity, confirming that structural modifications to the Licarin A have made improvements to its antimycobacterial properties.
Assuntos
Biofilmes/efeitos dos fármacos , Lignanas/química , Lignanas/farmacologia , Mycobacterium/efeitos dos fármacos , Micobactérias não Tuberculosas/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Claritromicina/farmacologia , Testes de Sensibilidade Microbiana , Myristica/química , Micobactérias não Tuberculosas/fisiologia , Sulfametoxazol/farmacologiaRESUMO
The search for compounds with new structural scaffolds is an important tool to the discovery of new drugs against Chagas disease. We report herein the synthesis of 1,2,3-triazoles obtained from eugenol and di-hydroeugenol and their in vitro and in vivo trypanocidal activity. These derivatives were obtained by a three-step objective route and were suitably characterized by 1 H and 13 C nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Two compounds (9 and 10) showed activity against epimastigote forms of Trypanosoma cruzi (Y strain) in the range 42.8-88.4 µM and were weakly toxic to cardiomyoblast cells (H9c2 cells). The triazole 10 was the most active derivative and could reduce more than 50% of parasitemia after a 100-mg/kg oral treatment of mice infected with T. cruzi. Molecular docking studies suggested this compound could act as a trypanocidal agent by inhibiting cruzain, an essential enzyme for T. cruzi metabolism, usually inhibited by triazole compounds.
Assuntos
Doença de Chagas/tratamento farmacológico , Inibidores de Cisteína Proteinase/síntese química , Proteínas de Protozoários/antagonistas & inibidores , Triazóis/síntese química , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Animais , Produtos Biológicos/química , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/farmacologia , Tripanossomicidas/farmacologiaRESUMO
Research has shown that chitosan induces plant stress tolerance and protection, but few studies have explored chemical modifications of chitosan and their effects on plants under water stress. Chitosan and its derivatives were applied (isolated or in mixture) to maize hybrids sensitive to water deficit under greenhouse conditions through foliar spraying at the pre-flowering stage. After the application, water deficit was induced for 15 days. Analyses of leaves and biochemical gas exchange in the ear leaf were performed on the first and fifteenth days of the stress period. Production attributes were also analysed at the end of the experiment. In general, the application of the two chitosan derivatives or their mixture potentiated the activities of the antioxidant enzymes superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase and guaiacol peroxidase at the beginning of the stress period, in addition to reducing lipid peroxidation (malonaldehyde content) and increasing gas exchange and proline contents at the end of the stress period. The derivatives also increased the content of phenolic compounds and the activity of enzymes involved in their production (phenylalanine ammonia lyase and tyrosine ammonia lyase). Dehydroascorbate reductase and compounds such as total soluble sugars, total amino acids, starch, grain yield and harvest index increased for both the derivatives and chitosan. However, the mixture of derivatives was the treatment that led to the higher increase in grain yield and harvest index compared to the other treatments. The application of semisynthetic molecules derived from chitosan yielded greater leaf gas exchange and a higher incidence of the biochemical conditions that relieve plant stress.
Assuntos
Antioxidantes/metabolismo , Quitosana/farmacologia , Fotossíntese/efeitos dos fármacos , Zea mays/crescimento & desenvolvimento , Antioxidantes/química , Ascorbato Peroxidases/metabolismo , Catalase/genética , Catalase/metabolismo , Quitosana/síntese química , Grão Comestível/efeitos dos fármacos , Grão Comestível/crescimento & desenvolvimento , Glutationa Redutase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Peroxidase/metabolismo , Folhas de Planta/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Água/química , Zea mays/efeitos dos fármacosRESUMO
Cancer is one of the most critical problems of public health in the world and one of the main challenges for medicine. Different biological effects have been reported for sulfonamide-based compounds including antibacterial, antifungal, and antitumor activities. Herein, a series of phenylpropanoid-based sulfonamides (4a, 4a', 4b, 4b', 5a, 5a', 5b and 5b') were synthesized and their cytotoxic activity was evaluated against four cell lines derived from human tumours (A549 - lung, MCF-7 - breast, Hep G2 - hepatocellular carcinoma, and HT-144-melanoma). Cell viability was significantly reduced in the MCF-7 cell line when compounds 4b, 4b' and 5a were used; IC50 values were lower than those found for their precursors (eugenol and dihydroeugenol) and sulfanilamide. We observed that 4b induced cell cycle arrest at G1/S transition. This is probably due to its ability to reduce cyclin D1 and cyclin E expression. Moreover, 4b also induced apoptosis in MCF-7 cells as demonstrated by an increase in the cell population positive for annexin V in treated cultures in comparison to the control group. Taken together, the data showed that 4b is a promising antitumor agent and it should be considered for further in vivo studies.
Assuntos
Antineoplásicos/farmacologia , Ciclina D1/metabolismo , Ciclina E/metabolismo , Proteínas Oncogênicas/metabolismo , Fenilpropionatos/farmacologia , Sulfonamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , HumanosRESUMO
Natural and synthetic coumarins have been described as prototypes of new drug candidates against Chagas' disease. During a typical screening with new compounds, we observed the potential of a new synthetic nitrobenzoylcoumarin (1) as trypanocidal against Trypanosoma cruzi epimastigotas. Then, we decided to prepare and evaluate a set of analogues from 1 to check the major structural requirements for trypanocidal activity. The structural variations were conducted in six different sites on the original compound and the best derivative (3) presented activity (IC50 28 ± 3 µM) similar to that of benznidazole (IC50 25 ± 10 µM). The enhancement of trypanocidal activity was conditioned to a change in the side chain at C6 (allyl to n-propyl group) and the preservation of coumarin nucleus and the nitrobenzoyl group at C3. Exposure of 3 to H9C2 cells showed low toxicity (CC50 > 200 µM) and its activity on T. cruzi amastigotes (IC50 13 ± 0.3 µM) encouraged us to perform an evaluation of its potential when given orally to mice infected with trypomastigote forms. Derivative 3 was able to reduce parasitemia when compared to the group of untreated animals. Taken together, these results show the potential therapeutic application of the synthetic coumarins.
Assuntos
Cumarínicos/química , Tripanossomicidas/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/veterinária , Cumarínicos/síntese química , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Feminino , Camundongos , Nitroimidazóis/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Seventeen new synthetic derivatives of eugenol (6, 8-15 and 8'-15') were planned following literature reports on antifungal activities of nitroeugenol and eugenol glucoside. The anti-Candida activity of these compounds was investigated by in vitro assay, and the cytotoxicity evaluation was performed with the most active compounds. The peracetylated glucosides presented better biological results than their hydroxylated analogues. The glucoside 11, a 4-nitrobenzamide, showed the best potency (MIC50 range 11.0-151.84 µm), the wider spectrum of action, and overall the best selectivity indexes, especially against C. tropicalis (~30) and C. krusei (~15). To investigate its possible mechanism of action, glucoside 11 was subjected to molecular docking studies with Candida sp. enzymes involved in ergosterol biosynthesis. Results have shown that the peracetyl glucosyl moiety and the 4-nitrobenzamide group in 11 are effectively involved in its high affinity with the active site of squalene epoxidase.