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Chagas disease (CD) remains neglected and causes high morbidity and mortality. The great difficulty is the lack of effective treatment. The current drugs cause side effects and have limited therapeutic efficacy in the chronic phase. This study aims to fulfil some gaps in studies of the natural substance lychnopholide nanoencapsulated LYC-PLA-PEG-NC (LYC-NC) and free (Free-LYC): the activity in epimastigotes and amastigotes to determine its selectivity index (SI), the therapeutic efficacy in mice infected with Colombian Trypanosoma cruzi strain and insight of the mechanism of LYC-NC action on T. cruzi. The SI was obtained by calculation of the ratio between the IC50 value toward H9c2 cells divided by the IC50 value in the anti-T. cruzi test. Infected Swiss mice were treated with 2 and 12 mg/kg/day via intravenous and oral, respectively, and the therapeutic efficacy was determined. The IC50 of LYC-NC and Free-LYC for epimastigotes of T. cruzi were similar. Both were active against amastigotes in cell culture, particularly Free-LYC. The SI of LYC-NC and Free-LYC were 45.38 and 32.11, respectively. LYC-NC 2 and 12 mg/kg/day cured parasitologically, 62.5% and 80% of the animals, respectively, infected with a strain resistant to treatment. The fluorescent NC was distributed in the cardiomyocyte cytoplasm, infected or not, and interacted with the trypomastigotes. Together, these results represent advances in demonstrating LYC as a potent new therapeutic option for treating CD.
Assuntos
Doença de Chagas , Nanocápsulas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Camundongos , Nifurtimox/uso terapêutico , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Doença de Chagas/tratamento farmacológico , Poliésteres/farmacologia , Poliésteres/uso terapêutico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêuticoRESUMO
Four hybrid steroid dimers were obtained by BF3·Et2O-catalyzed aldol condensation of acetylated steroid sapogenins with 2-formyl-estradiol diacetate. The structures of the obtained dimers were unambiguously established by NMR. The hybrid dimers 9a (IC50 18.37⯵M) and 9c (IC50 9.4⯵M) with the 5α configuration at the A/B rings junction showed the higher cytotoxicity against HeLa, with selectivity index of 4.36 and 11.8 respectively. The presence of a carbonyl function at position C-12 produced the highest cytotoxic effect, which is in line with our previous reports.
RESUMO
We present the synthesis and characterization of organic Salphen compounds containing bromine substituents at the para/ortho-para positions, in their symmetric and non-symmetric versions, and describe the X-ray structure and full characterization for the new unsymmetrical varieties. We report for the first time antiproliferative activity in metal-free brominated Salphen compounds, by evaluations in four human cancer cell lines, cervix (HeLa), prostate (PC-3), lung (A549) and colon (LSâ 180) and one non-cancerous counterpart (ARPE-19). We assessed inâ vitro cell viability against controls using the MTT assay ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)) and determined the concentration required for 50 % growth inhibition (IC50 ), together with their selectivity vs. non-cancerous cells. We found promising results against prostate (9.6â µM) and colon (13.5â µM) adenocarcinoma cells. We also found a tradeoff between selectivity (up to 3-fold vs. ARPE-19) and inhibition, depending upon the symmetry and bromine-substitution of the molecules, showing up to 20-fold higher selectivity vs. doxorubicin controls.
Assuntos
Antineoplásicos , Bromo , Masculino , Feminino , Humanos , Bromo/farmacologia , Células HeLa , Fenilenodiaminas/farmacologia , Antineoplásicos/química , Proliferação de Células , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Drug therapy for leishmaniasis remains a major challenge as currently available drugs have limited efficacy, induce serious side-effects and are not accessible to everyone. Thus, the discovery of affordable drugs is urgently needed. Chalcones present a great potential as bioactive agents due to simple structure and functionalization capacity. The antileishmanial activity of different natural and synthetic chalcones have been reported. Here we report the synthesis of twenty-five novel prenylated chalcones that displayed antiparasitic activity in Leishmania mexicana. All the chalcones were evaluated at 5 µg/mL and eleven compounds exhibited a metabolic inhibition close to or exceeding 50%. Compounds 49, 30 and 55 were the three most active with IC50 values < 10 µM. These chalcones also showed the highest selectivity index (SI) values. Interestingly 49 and 55 possessing a substituent at a meta position in the B ring suggests that the substitution pattern influences antileishmanial activity. Additionally, a tridimensional model of fumarate reductase of L. mexicana was obtained by homology modeling. Docking studies suggest that prenylated chalcones could modulate fumarate reductase activity by binding with good affinity to two binding sites that are critical for the target. In conclusion, the novel prenylated chalcones could be considered as promising antileishmanial agents.
Assuntos
Antiprotozoários , Chalconas , Leishmaniose , Humanos , Chalconas/química , Succinato Desidrogenase , Éteres , Antiprotozoários/química , Leishmaniose/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Cancer is the second death cause worldwide, with breast and colon cancer among the most prevalent types. Traditional treatment strategies have several side effects that inspire the development of novel anticancer agents derived from natural sources, like chalcone derivatives. For this investigation, twenty-three chalcones (4a-w) were synthesized and evaluated as antiproliferative agents against MCF-7 and Caco-2 cells, finding three and two compounds with similar or higher antiproliferative activity than daunorubicin, while only two chalcones showed better selectivity indexes than daunorubicin on MCF-7. From these results, we developed good-performance QSAR models (r > 0.850, q2>0.650), finding several structural features that could modify chalcone activity and selectivity. According to these models, chalcones 4w and 4t have high potency and selectivity against Caco-2 and MCF-7, respectively, which make them attractive candidates for hit-to-lead development of ROS-independent pro apoptotic agents.
Assuntos
Antineoplásicos , Chalcona , Chalconas , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CACO-2 , Proliferação de Células , Chalcona/farmacologia , Chalconas/química , Chalconas/farmacologia , Daunorrubicina/farmacologia , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Canine mammary carcinoma (CMC) is one of the major health threats in dogs. The oncolytic virotherapy is a promising strategy to treat canine as well as human cancer patients with non-pathogenic replicating viruses. Here, we evaluated the antitumor activity of one lentogenic, non-lytic Newcastle disease virus (NDV) LaSota strain expressing GFP (NDV-GFP) on five different CMCs and one non-tumorigenic cell line, regarding cell viability, cell death, selectivity index, morphology, global and target gene expression analysis. As evidenced by the selectivity index, all CMC cell lines were more susceptible to NDV-GFP in comparison with the non-tumorigenic cells (~3.1× to ~78.7×). In addition, the oncolytic effect of NDV-GFP was more evident in more malignant CMC cells. Also, we observed an inverse association of the IFN pathway expression and the susceptibility to NDV. The downregulated genes in NDV-GFP-sensitive cells were functionally enriched for antiviral mechanisms by interferon and immune system pathways, demonstrating that these mechanisms are the most prominent for oncolysis by NDV. To our knowledge, this is the first description of oncolysis by an NDV strain in canine mammary cancer cells. We also demonstrated specific molecular pathways related to NDV susceptibility in these cancer cells, opening the possibility to use NDV as a therapeutic-targeted option for more malignant CMCs. Therefore, these results urge for more studies using oncolytic NDVs, especially considering genetic editing to improve efficacy in dogs.
Assuntos
Doenças do Cão , Neoplasias Mamárias Animais/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Antivirais , Doenças do Cão/terapia , Cães , Feminino , Interferons , Vírus da Doença de Newcastle , Terapia Viral Oncolítica/veterinária , Replicação ViralRESUMO
The pharmacological potential of drugs must be evaluated to establish their potential therapeutic benefits and side effects. This evaluation includes assessment of the effects of hepatic enzymes that catalyse their metabolic activation. Previously, our research group synthesized and characterized a set of synthetic 3-alkyl pyridine alkaloid (3-APA) analogues that cause in vitro cytotoxic, genotoxic, and mutagenic effects in various human cancer cell lines. The present study aimed to evaluate these activities with the two most promising synthetic 3-APAs (3-APA 1 and 3-APA 2) against cell lines derived from breast cancer (MDA-MB-231), ovarian cancer (TOV-21 G) and lung fibroblasts (WI-26-VA4) with and without metabolic activation (S9 fraction). The cytotoxicity of the compounds was evaluated employing MTT and clonogenic assays. In addition, comet assays, γH2AX immunocytochemistry labelling assays and cytokinesis-block micronucleus tests were carried out to evaluate the potential of these compounds to induce chromosomal damage. The results obtained in the MTT assay showed that compound 3-APA 2 exhibited high selectivity index (SI) values (ranging between 21.0 and 92.6). In addition, the cytotoxicity of the compounds was clearly enhanced by metabolic activation. Moreover, both compounds were genotoxic and induced double-strand breaks in DNA and chromosomal lesions with and without S9. The cancer cell lines tested showed higher genotoxic sensitivity to the compounds than did the non-tumour cell line used as a reference. The genotoxic and mutagenic effects of the compounds were potentiated in experiments with metabolic activation. The data obtained in this study indicate that compound 3-APA 2 is more active against the human cancer cell lines tested, both with and without metabolic activation, and can therefore be considered a candidate drug to treat human ovarian and breast cancer.
Assuntos
Ativação Metabólica , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Citocinese/efeitos dos fármacos , Dano ao DNA , Mutagênicos/farmacologia , Neoplasias/patologia , Ensaio Cometa , Humanos , Testes para Micronúcleos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Células Tumorais CultivadasRESUMO
Trypanosoma cruzi is the agent of Chagas disease, an infection that affects around 8 million people worldwide. The search for new anti-T. cruzi drugs are relevant, mainly because the treatment of this disease is limited to two drugs. The objective of this study was to investigate the trypanocidal and cytotoxic activity and elucidate the chemical profile of extracts from the roots of the Lonchocarpus cultratus. Roots from L. cultratus were submitted to successive extractions with hexane, dichloromethane, and methanol, resulting in LCH, LCD, and LCM extracts, respectively. Characterization of extracts was done using 1H-RMN, 13C-RMN, CC and TLC. Treatment of T. cruzi forms (epimastigotes, trypomastigotes, and amastigotes) with crescent concentrations of LCH, LCD, and LCM was done for 72, 48, and 48 h, respectively. After this, the percentage of inhibition and IC50/LC50 were calculated. Benznidazole was used as a positive control. Murine macrophages were treated with different concentrations of both extracts for 48 h, and after, the cellular viability was determined by the MTT method and CC50 was calculated. The chalcones derricin and lonchocarpine were identified in the hexane extract, and for the first time in the genus Lonchocarpus, the presence of a dihydrolonchocarpine derivative was observed. Other chalcones such as isocordoin and erioschalcone B were detected in the dichloromethane extract. The dichloromethane extract showed higher activity against all tested forms of T. cruzi than the other two extracts, with IC50 values of 10.98, 2.42, and 0.83 µg/mL, respectively; these values are very close to those of benznidazole. Although the dichloromethane extract presented a cytotoxic effect against mammalian cells, it showed selectivity against amastigotes. The methanolic extract showed the lowest anti-T. cruzi activity but was non-toxic to peritoneal murine macrophages. Thus, the genus Lonchocarpus had demonstrated in the past action against epimastigotes forms of T. cruzi but is the first time that the activity against infective forms is showed, which leading to further studies with in vivo tests.
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Diaphania hyalinata (Linnaeus, 1767) is one of the main pests of the cucurbit crops. Biological control and botanicals are used in integrated pest management (IPM), especially in agro-ecological agricultures where the use of synthetic pesticides is restricted. Toxicological effects of plant essential oils on target and nontarget organisms should be evaluated to determine its use in IPM. The toxicity of ginger, peppermint, oregano, and thyme essential oils to D. hyalinata eggs, larvae, and pupae and their selectivity to the parasitoid Trichospilus pupivorus and the LC50, LC99 and the relative selectivity index (RSI) of these botanicals were determined. The eggs of D. hyalinata were more sensitive to the botanicals applied than its larvae and pupae, with higher toxicity of oregano and thyme essential oils, followed by those of peppermint and ginger. Topical application was the least toxic method to D. hyalinata larvae. Ginger, peppermint, and thyme essential oils were more toxic by ingestion and oregano by contact to D. hyalinata larvae. The essential oil concentrations applied to D. hyalinata pupae prevent the emergence of adults of this insect with the oregano essential oil showing the greatest toxicity. Peppermint, ginger, thyme, and oregano essential oils were selective to T. pupivorus with RSI50 of 5.40, 1.38, 8.15, and 6.98 and RSI99 of 1.54, 2.53, 3.90, and 4.16 respectively. The ginger, peppermint, oregano, and thyme essential oils were toxic to immature D. hyalinata and selective to T. pupivorus females presenting potential as an alternative control in the IPM of this pest in Cucurbitaceae crops.
Assuntos
Himenópteros , Mariposas , Óleos Voláteis , Thymus (Planta) , Animais , Feminino , Larva , Óleos de PlantasRESUMO
The aim of this study was to determine, first, the chemical composition of Aloysia polystachya (Griseb) Moldenke essential oil, from leaves harvested in central Chile; and second, its antioxidant and cytotoxic activity. Eight compounds were identified via gas chromatography-mass spectrometry (GC-MS) analyses, with the most representative being R-carvone (91.03%), R-limonene (4.10%), and dihydrocarvone (1.07%). For Aloysia polystachya essential oil, antioxidant assays (2,2-diphenyl-1-picrylhydrazyl (DPPH), H2O2, ferric reducing antioxidant power (FRAP), and total reactive antioxidant potential (TRAP)) showed good antioxidant activity compared to commercial antioxidant controls; and anti-proliferative assays against three human cancer cell lines (colon, HT-29; prostate, PC-3; and breast, MCF-7) determined an IC50 of 5.85, 6.74, and 9.53 µg/mL, and selectivity indices of 4.75, 4.12, and 2.92 for HT-29, PC-3, and MCF-7, respectively. We also report on assays with CCD 841 CoN (colon epithelial). Overall, results from this study may represent, in the near future, developments for natural-based cancer treatments.
Assuntos
Antioxidantes/química , Proliferação de Células/efeitos dos fármacos , Monoterpenos Cicloexânicos/análise , Limoneno/análise , Verbenaceae/metabolismo , Linhagem Celular Tumoral , Chile , Cromatografia Gasosa-Espectrometria de Massas , Células HT29 , Humanos , Peróxido de Hidrogênio , Concentração Inibidora 50 , Células MCF-7 , Óleos Voláteis , Células PC-3 , Extratos VegetaisRESUMO
The available drugs for treating Leishmaniasis and American trypanosomiasis have high toxicity and multiple side effects, among other problems. More effective and less toxic treatments are urgently needed. A series of chalcones that contained a prenyloxy or geranyloxy substituent was synthesized and characterized. Each substituent was attached to the A ring in some compounds and to the B ring in others, with additional substituents placed on the chalcone moiety. The present aim was to evaluate the effect of the substitution pattern on leishmanicidal and trypanocidal activity. When tested at a single concentration, the compounds exerting a metabolic inhibition close to or exceeding 50% for Leishmania mexicana were 11, 17 and 12, and for Trypanosoma cruzi were 11, 17, 15 and 26. Upon determining the selectivity index (SI =IC50/CC50), the values were 80.9, 1.24 and 55.12 for 11, 17 and 12 (respectively) versus L. mexicana, and 75.1, 1.43, 27.36 and 33.52 for 11, 17, 15 and 26 (respectively) versus T. cruzi. Structural isomers 11 and 17 showed activity for both the L. mexicana and T. cruzi strains, though the greater cytotoxic activity of 17 led to a lower SI. Compounds 12, 15 and 26 were species specific. For T. cruzi, the SI was higher for 11, 15 and 26 than for the reference drugs nifurtimox and benznidazole. The examination of promastigote morphology after exposing L. mexicana and T. cruzi to 11 revealed a decrease in cell density. The current findings suggest that 11 could be a useful lead compound for further SAR studies.
Assuntos
Antiprotozoários/síntese química , Chalconas/síntese química , Chalconas/farmacologia , Desenho de Fármacos , Tripanossomicidas/síntese química , Animais , Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Humanos , Leishmania mexicana/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Schinopsis brasiliensis is a plant typically found in the caatinga biome (northeastern Brazil). Its leaves and bark have been used for the treatment of health dysfunctions such as cough, influenza, diarrhea, throat inflammation, and sexual impotence. However, there is a lack of knowledge regarding the chemical composition and pharmacological activities of this plant. High-performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-QTOF-MSE) allowed the partial identification of 33 compounds, including isomers from leaf, branch, and bark samples, with 16 compounds reported for the first time (corilagin, chlorogenic acid, and quercetin derivatives) in S. brasiliensis. Principal component analysis efficiently distinguished the respective parts of the plant. Orthogonal partial least squares discriminatory analysis, together with the variable importance in projection and S-Plot graphs were used to identify 23 biomarker compounds associated with cytotoxic activity against a colorectal cancer cell line.
Assuntos
Anacardiaceae/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Flavonóis/análise , Compostos Fitoquímicos/análise , Anacardiaceae/química , Animais , Brasil , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Flavonóis/metabolismo , Flavonóis/toxicidade , Humanos , Espectrometria de Massas , Metaboloma/fisiologia , Camundongos , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/toxicidade , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Análise de Componente PrincipalRESUMO
The identification of specific therapeutic targets and the development of new drugs against leishmaniasis are urgently needed, since chemotherapy currently available for its treatment has several problems including many adverse side effects. In an effort to develop new antileishmanial drugs, in the present study a series of 28 N-benzyl-1H-benzimidazol-2-amine derivatives was synthesized and evaluated in vitro against Leishmania mexicana promastigotes. Compounds 7 and 8 with the highest antileishmanial activity (micromolar) and lower cytotoxicity than miltefosine and amphotericin B were selected to evaluate their activity against L. braziliensis 9and L. donovani, species causative of mucocutaneous and visceral leishmaniasis, respectively. Compound 7 showed significantly higher activity against L. braziliensis promastigotes than compound 8 and slightly lower than miltefosine. Compounds 7 and 8 had IC50 values in the micromolar range against the amastigote of L. mexicana and L. braziliensis. However, both compounds did not show better activity against L. donovani than miltefosine. Compound 8 showed the highest SI against both parasite stages of L. mexicana. In addition, compound 8 inhibited 68.27% the activity of recombinant L. mexicana arginase (LmARG), a therapeutic target for the treatment of leishmaniasis. Docking studies were also performed in order to establish the possible mechanism of action by which this compound exerts its inhibitory effect. Compound 8 shows promising potential for the development of more potent antileishmanial benzimidazole derivatives.
Assuntos
Antiprotozoários/farmacologia , Benzimidazóis/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania donovani/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Sequência de Aminoácidos , Anfotericina B/farmacologia , Animais , Antiprotozoários/toxicidade , Arginase/antagonistas & inibidores , Arginase/química , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/toxicidade , Linhagem Celular , Concentração Inibidora 50 , Leishmania mexicana/enzimologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Leishmaniose Mucocutânea/tratamento farmacológico , Leishmaniose Mucocutânea/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Macrófagos/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Alinhamento de SequênciaRESUMO
BACKGROUND: Excoecaria lucida Sw. (Euphorbiaceae) is a plant conventionally used throughout the Caribbean in the treatment of infectious diseases. OBJECTIVE: To evaluate, using bioassay-guided fractionation, the in vitro cytotoxicity and antimicrobial activity of E. lucida leaves. MATERIALS AND METHODS: A 95% ethanol crude extract was dried and fractionated by solid-liquid separation in four phases (hexane, dichloromethane, ethyl acetate, and butanol). Antimicrobial activity (3 bacteria, 6 yeasts, and 2 fungi) was evaluated by the dilution method with resazurin (2048, 512, 128, 32, and 8 µg/mL). The cytotoxicity assays were evaluated in two cell lines: MRC-5 and RAW 264.7; calculating the selectivity index. Assays were performed for the total extract, the isolated compound with the highest yield, and the ethyl acetate and butanol phases. Isolated compounds were characterized by nuclear magnetic resonance and mass spectrometry techniques. RESULTS: Fractionation process led to the isolation of ellagic acid (784.29 mg), 3,3',4'-tri-O-methyl ellagic 4-O-ß-D-glucopyranoside acid (6.1 mg), and corilagin (6.91 mg). The most active were ethyl acetate phase and ellagic acid with IC50= 128 µg/mL against seven and five different species of microorganisms, respectively. The total extract (IC50=512 µg/mL) and the ethyl acetate phase (IC50=128 µg/mL) were cytotoxic in both cell lines, while butanol phase and ellagic acid both with IC50>2048 µg/mL seemed to be safer. CONCLUSIONS: The results obtained indicate that the Excoecaria leaves can be conventionally used as antimicrobial, but it should be present that some cytotoxicity could appear. In addition, the three identified compounds were reported for the first time in the species. SUMMARY: Excoecaria lucida leaves (Euphorbiaceae) are used by the Cuban population due to their antimicrobial activity. This ethnopharmacological knowledge is confirmed by the integrated antibacterial and antifungal in vitro screening developed, using the bioassay-guided fractionation method.Abbreviations Used: MRC-5-SV2: Diploid human lung fibroblasts cells, RAW 264.7: Murine macrophages cells, IC50: Inhibitory Concentration 50%, ATCC: American Type Culture Collection, CCEBI: Culture Collection of Industrial Biotechnology Center, CECT: Spanish Culture Collection Type, CFU: Colony forming units, CC50: 50% cytotoxic concentration, CO2: Carbon dioxide, SI: Selectivity index, IR: Infrared spectroscopy, 1H NMR: Nuclear Magnetic Resonance of hydrogen, 13C NMR: Nuclear Magnetic Resonance of carbon, HMQC: Heteronuclear Multiple-Quantum Correlation, HMBC: Heteronuclear Multiple Bond Correlation, COSY: Correlation Spectroscopy, NOESY: Nuclear Overhauser Effect Spectroscopy, KBr: Potassium bromide, DMSO-D6: Deuterated dimethyl sulfoxide, LC.MS: Liquid Chromatography-Mass Spectrometry, [α]D: Optical rotation, EL1: ellagic acid, EL2: 3,3',4'-tri-O-methyl ellagic 4-O-ß-D-glucopyranoside acid, EL3: corilagin, Active (+), inactive (-).
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Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters (7, 11, 13, and 17), one ether (23), and three amino-ethers (30, 31, and 33) exhibited moderate activity against methicillin-resistant Staphylococcus aureus, whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium. Additionally, nineteen meso-DGA derivatives displayed moderate to potent activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50µg/mL. Seven meso-DGA derivatives bearing amino-ethers (26-31 and 33) exhibited the lowest MICs against M. tuberculosis H37Rv and G122 strains, with 31 being as potent as ethambutol (MICs of 3.125 and 6.25µg/mL). The presence of positively charged group precursors possessing steric and hydrophobic features (e.g. N-ethylpiperidine moieties in meso-31) resulted essential to significantly increase the antimycobacterial properties of parent meso-DGA as supported by the R-group pharmacophoric and field-based QSAR analyses. To investigate the safety profile of the antimycobacterial compounds, cytotoxicity on Vero cells was determined. The amino-ether 31 exhibited a selectivity index value of 23, which indicate it was more toxic to M. tuberculosis than to mammalian cells. Therefore, 31 can be considered as a promising antitubercular agent for further studies.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Guaiacol/análogos & derivados , Lignanas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Guaiacol/síntese química , Guaiacol/química , Guaiacol/farmacologia , Lignanas/síntese química , Lignanas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Células VeroRESUMO
CONTEXT: Plants of the Piperaceae family produce piplartine that was used to synthesize the cinnamides. OBJECTIVE: To assess the effects of piplartine (1) and cinnamides (2-5) against the protozoa responsible for malaria and leishmaniasis, and peritoneal cells of Swiss mice. MATERIALS AND METHODS: Cultures of Leishmania amazonensis, Plasmodium falciparum-infected erythrocytes, and peritoneal cells were incubated, in triplicate, with different concentrations of the compounds (0 to 256 µg/mL). The inhibitory concentration (IC50) in L. amazonensis and cytotoxic concentration (CC50) in peritoneal cell were assessed by the MTT method after 6 h of incubation, while the IC50 for P. falciparum-infected erythrocytes was determined by optical microscopy after 48 or 72 h of incubation; the Selectivity Index (SI) was calculated by CC50/IC50. RESULTS: All compounds inhibited the growth of microorganisms, being more effective against P. falciparum after 72 h of incubation, especially for the compounds 1 (IC50 = 3.2 µg/mL) and 5 (IC50 = 6.6 µg/mL), than to L. amazonensis (compound 1 = 179.0 µg/mL; compound 5 = 106.0 µg/mL). Despite all compounds reducing the viability of peritoneal cells, the SI were <10 to L. amazonensis, whereas in the cultures of P. falciparum the SI >10 for the piplartine (>37.4) and cinnamides 4 (>10.7) and 5 (= 38.4). DISCUSSION AND CONCLUSION: The potential of piplartine and cinnamides 4 and 5 in the treatment of malaria suggest further pre-clinical studies to evaluate their effects in murine malaria and to determine their mechanisms in cells of the immune system.
Assuntos
Cinamatos/farmacologia , Leishmania/efeitos dos fármacos , Piperidonas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/administração & dosagem , Cinamatos/química , Relação Dose-Resposta a Droga , Eritrócitos/parasitologia , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Peritônio/citologia , Peritônio/efeitos dos fármacos , Piperaceae/química , Piperidonas/administração & dosagem , Piperidonas/isolamento & purificação , Fatores de TempoRESUMO
Understanding the nutritional basis of food selection is fundamental to evaluate dietary patterns and foraging strategies in primates. This research describes the phytochemical composition of the foods consumed by two groups of Mexican black howler monkeys (Alouatta pigra) during a 15-month field study, and examines how plant nutritional chemistry affected food choice. Based on indices of selectivity that reflected seasonal changes in the amount of different phenophases of the most consumed plant species and their availability in the environment, we found that, in general, howlers did not preferentially select food items based on their concentrations of protein, sugar, energy, or their protein-to-fiber ratio. During only one season of the year, the nortes (October-January), there was evidence for selectivity. During this period, selectivity indices correlated positively with the lipid content of foods ingested. However, a strategy of selecting fruits high in lipids (21-41% dry matter) coincided with the consumption of a leaf-based diet (based on estimates of the dry weight of food ingested), suggesting that during this season howlers interchanged lipids with sugars to obtain energy and possibly to balance the higher protein intake obtained by the increased leaf consumption. Overall, these data did not support the prediction that food choice in this howler population was strongly correlated with particular nutrients, and suggest that balancing a suite of nutrients by consuming plants that vary widely in their composition may be an important strategy for howler monkeys. Am. J. Primatol. 79:e22524, 2017. © 2015 Wiley Periodicals, Inc.
Assuntos
Alouatta , Preferências Alimentares , Lipídeos , Animais , Dieta , FrutasRESUMO
ResumenLas plantas carnívoras del género Utricularia, capturan un amplio ámbito de organismos acuáticos. La mayoría se desarrollan en ambientes con carencias de nutrientes y tienen la capacidad de cambiar las condiciones de su microambiente. El objetivo de la presente investigación fue estudiar la selectividad, en la captura de zooplancton por Utricularia foliosa en la Ciénaga de Paredes; entre febrero y noviembre 2014. Se determinó si existe selección en los recursos alimentarios de la planta con el índice de Czekanowski y el grado de selección, a través de los índices de Savage e Ivlev. Se estableció la relación existente entre los patrones de captura y selección del zooplancton, con variables físicoquímicas y la disponibilidad de nutrientes en la Ciénaga. En nuestros resultados, el índice de Czekanowski evidenció selección, en los recursos alimentarios de la planta, durante todo el pulso de inundación, con valores entre 0.28 y 0.41. Se encontró selección positiva significativa, con el índice de Savage, para los géneros Lecane sp., Alona sp., Ceriodaphnia sp., y Bosmina sp. (p < 0.05). Se obtuvieron resultados similares, con el índice de Ivlev. La intensidad en la selección de los géneros varió entre periodos hidrológicos y por periodos de aguas altas y bajas. Se identificó que los cambios en la concentración de amoniaco y nitrato, además de la variación en la conductividad eléctrica de la ciénaga influencian la captura que realiza U. foliosa. Este es el primer trabajo que permite dar un acercamiento al entendimiento de la selección de recursos alimentarios dentro de la especie a través de índices de selectividad y uno de los pocos para el género.
Abstract:Utricularia is a genus of carnivorous plants that capture a wide range of aquatic organisms. Most of these plants grow in environments with nutrients deficiency and have the ability to change the conditions of their microenvironment. The aim of this research was to study the selectivity in the zooplankton capture by Utricularia foliosa in the Ciénaga de Paredes. Our study was undertaken between February and November, 2014. We tried to determine if there is selection in the plant's food resources by the Czekanowski's index, and the selection degree by the Savage and Ivlev's indexes. Additionally, we studied the possible relation between the patterns of zooplankton capture and selection, with physicochemical variables in the swamp. The Czekanowski's index showed a food selection in plant resources throughout the flood pulse, with values between 0.28 and 0.41. We also found a significant positive selection with Savage's index for Lecane sp., Alona sp., Ceriodaphnia sp., and Bosmina sp. (p < 0.05); similar results were obtained with Ivlev's index. The intensity in the selection of each captured genus varied significantly between hydrological periods and between high and low water levels in the swamp. It was possible to identify some changes in the ammonia and nitrate concentration and some variability in the electric conductivity of the swamp, which influenced the captures made by U. foliosa. This is the first paper that allows an approach to understand the selection of food resources for the species, using a selectivity index, and one of the few for the genus. Rev. Biol. Trop. 64 (3): 1297-1310. Epub 2016 September 01.
Assuntos
Animais , Zooplâncton/classificação , Lamiales/fisiologia , Estações do Ano , Temperatura , Zooplâncton/fisiologia , Análise por Conglomerados , Colômbia , Estatísticas não Paramétricas , Rios/química , Preferências AlimentaresRESUMO
Infusions of Aspidosperma nitidum (Apocynaceae) wood bark are used to treat fever and malaria in the Amazon Region. Several species of this family are known to possess indole alkaloids and other classes of secondary metabolites, whereas terpenoids, an inositol and the indole alkaloids harmane-3 acid and braznitidumine have been described in A. nitidum . In the present study, extracts from the wood bark, leaves and branches of this species were prepared for assays against malaria parasites and cytotoxicity testing using human hepatoma and normal monkey kidney cells. The wood bark extracts were active against Plasmodium falciparum and showed a low cytotoxicity in vitro, whereas the leaf and branch extracts and the pure alkaloid braznitidumine were inactive. A crude methanol extract was subjected to acid-base fractionation aimed at obtaining alkaloid-rich fractions, which were active at low concentrations against P. falciparum and in mice infected with and sensitive Plasmodium berghei parasites. Our data validate the antimalarial usefulness of A. nitidum wood bark, a remedy that can most likely help to control malaria. However, the molecules responsible for this antimalarial activity have not yet been identified. Considering their high selectivity index, the alkaloid-rich fractions from the plant bark might be useful in the development of new antimalarials.