Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Curr Protein Pept Sci ; 25(1): 12-26, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37653631

RESUMO

Glioblastoma multiforme (GBM) is the most common type of cancer that affects the central nervous system (CNS). It currently accounts for about 2% of diagnosed malignant tumors worldwide, with 296,000 new cases reported per year. The first-choice treatment consists of surgical resection, radiotherapy, and adjuvant chemotherapy, which increases patients' survival by 15 months. New clinical and pre-clinical research aims to improve this prognosis by proposing the search for new drugs that effectively eliminate cancer cells, circumventing problems such as resistance to treatment. One of the promising therapeutic strategies in the treatment of GBM is the inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway, which is closely related to the process of tumor carcinogenesis. This review sought to address the main scientific studies of synthetic or natural drug prototypes that target specific therapy co-directed via the PI3K pathway, against human glioblastoma.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia
2.
Fundam Clin Pharmacol ; 38(1): 84-98, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37649138

RESUMO

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.


Assuntos
Anti-Infecciosos , Tiadiazinas , Antibacterianos/farmacologia , Tiadiazinas/farmacologia , Tiadiazinas/química , Norfloxacino/farmacologia , Anti-Inflamatórios , Testes de Sensibilidade Microbiana
3.
Mini Rev Med Chem ; 23(11): 1193-1221, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37424359

RESUMO

Infections caused by the Hepatitis C virus (HCV) affect around 70 million people worldwide, leading to serious liver problems, such as fibrosis, steatosis, and cirrhosis, in addition to progressing to hepatocellular carcinoma and becoming globally the main cause of liver disease. Despite great therapeutic advances in obtaining pan-genotypic direct-acting antivirals (DAAs), around 5-10% of affected individuals are unable to eliminate the virus by their own immune system's activity. Still, there are no licensed vaccines so far. In this context, the orchestrated process of virus entry into host cells is a crucial step in the life cycle and the infectivity capability of most viruses. In recent years, the entry of viruses has become one of the main druggable targets used for designing effective antiviral molecules. This goal has come to be widely studied to develop pharmacotherapeutic strategies against HCV, combined or not with DAAs in multitarget approaches. Among the inhibitors found in the literature, ITX 5061 corresponds to the most effective one, with EC50 and CC50 values of 0.25 nM and >10 µM (SI: 10,000), respectively. This SRBI antagonist completed the phase I trial, constituting a promising compound against HCV. Interestingly, chlorcyclizine (an antihistamine drug) showed action both in E1 apolipoproteins (EC50 and CC50 values of 0.0331 and 25.1 µM, respectively), as well as in NPC1L1 (IC50 and CC50 values of 2.3 nM and > 15 µM, respectively). Thus, this review will discuss promising inhibitors targeting HCV entry, discussing their SAR analyzes, recent contributions, and advances in this field.


Assuntos
Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Humanos , Hepacivirus , Antivirais/farmacologia , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C/tratamento farmacológico , Internalização do Vírus , Neoplasias Hepáticas/tratamento farmacológico
4.
Fundam Clin Pharmacol ; 37(3): 619-628, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36579760

RESUMO

In the present study, we examined the antinociceptive and anti-inflammatory activities of a guanylhydrazone derivative, (E)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-guanylhydrazone hydrochloride (LQM10), in mice. The antinociceptive effect was determined by assessing behavioural responses in different pain models, while anti-inflammatory activity was examined in carrageenan-induced pleurisy. Intraperitoneal LQM10 administration reduced the acetic acid-induced nociceptive behaviour, a phenomenon that was unaltered by pretreatment with yohimbine, atropine, naloxone or glibenclamide. In the formalin assay, LQM10 reduced nociceptive behaviour only in the second phase, indicating an inhibitory effect on inflammatory pain. LQM10 did not alter the pain latency in the hot plate assay and did not impact the locomotor activity of mice in the rotarod assay. In the carrageenan-induced pleurisy assay, LQM10 treatment inhibited critical events involved in inflammatory responses, namely, leucocyte recruitment, plasma leakage and increased inflammatory mediators (tumour necrosis factor Like Properties of Chalchones and Flavonoid Derivatives [TNF]-α and interleukin [IL]-1ß) in the pleural exudate. Overall, these results indicate that LQM10 exhibits antinociceptive effects associated with peripheral mechanisms and anti-inflammatory activity mediated via a reduction in leucocyte migration and proinflammatory mediators, rendering this compound a promising candidate for treating pain and inflammatory process.


Assuntos
Analgésicos , Pleurisia , Animais , Camundongos , Analgésicos/efeitos adversos , Carragenina , Nociceptividade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Pleurisia/induzido quimicamente , Pleurisia/tratamento farmacológico , Fator de Necrose Tumoral alfa , Edema/induzido quimicamente , Edema/tratamento farmacológico
5.
Curr Top Med Chem ; 22(29): 2435-2462, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36415099

RESUMO

The Flaviviridae virus family consists of the genera Hepacivirus, Pestivirus, and Flavivirus, with approximately 70 viral types that use arthropods as vectors. Among these diseases, dengue (DENV) and zika virus (ZIKV) serotypes stand out, responsible for thousands of deaths worldwide. Due to the significant increase in cases, the World Health Organization (WHO) declared DENV a potential threat for 2019 due to being transmitted by infected travelers. Furthermore, ZIKV also has a high rate of transmissibility, highlighted in the outbreak in 2015, generating consequences such as Guillain-Barré syndrome and microcephaly. According to clinical outcomes, those infected with DENV can be asymptomatic, and in other cases, it can be lethal. On the other hand, ZIKV has severe neurological symptoms in newborn babies and adults. More serious symptoms include microcephaly, brain calcifications, intrauterine growth restriction, and fetal death. Despite these worrying data, no drug or vaccine is approved to treat these diseases. In the drug discovery process, one of the targets explored against these diseases is the NS2B-NS3 complex, which presents the catalytic triad His51, Asp75, and Ser135, with the function of cleaving polyproteins, with specificity for basic amino acid residues, Lys- Arg, Arg-Arg, Arg-Lys or Gln-Arg. Since NS3 is highly conserved in all DENV serotypes and plays a vital role in viral replication, this complex is an excellent drug target. In recent years, computer-aided drug discovery (CADD) is increasingly essential in drug discovery campaigns, making the process faster and more cost-effective, mainly explained by discovering new drugs against DENV and ZIKV. Finally, the main advances in computational methods applied to discover new compounds against these diseases will be presented here. In fact, molecular dynamics simulations and virtual screening is the most explored approach, providing several hit and lead compounds that can be used in further optimizations. In addition, fragment-based drug design and quantum chemistry/molecular mechanics (QM/MM) provides new insights for developing anti-DENV/ZIKV drugs. We hope that this review offers further helpful information for researchers worldwide and stimulates the use of computational methods to find a promising drug for treating DENV and ZIKV.


Assuntos
Dengue , Microcefalia , Infecção por Zika virus , Zika virus , Recém-Nascido , Humanos , Infecção por Zika virus/tratamento farmacológico , Replicação Viral , Dengue/tratamento farmacológico , Proteínas não Estruturais Virais
6.
Mini Rev Med Chem ; 22(22): 2896-2924, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35379146

RESUMO

Ebola Virus (EBOV) is an infectious disease that mainly affects the cardiovascular system. It belongs to the Filoviridae family, consisting of filamentous envelopes and non-segmented negative RNA genome. EBOV was initially identified in Sudan and Zaire (now named the Democratic Republic of Congo) around 1967. It is transmitted mainly by contact with secretions (blood, sweat, saliva, and tears) from infected wild animals, such as non-human primates and bats. It has gained more prominence in recent years due to the recent EBOV outbreaks that occurred from 2013 to 2016, resulting in approximately 28,000 infected individuals, with a mortality rate of 40- 70%, affecting mainly Liberia, Guinea, and Sierra Leone. Despite these alarming levels, there is still no FDA-approved drug for the effective treatment of these diseases. The most advanced drug to treat EBOV is remdesivir. However, it is a high-cost drug and is available only for intravenous use. In this sense, more investments are needed in the research focused on the development of new antiviral drugs. In this context, medicinal chemistry strategies have been improving and increasingly discovering new hits that can be used in the future as a treatment against these diseases. Thus, this review will address the main advances in medicinal chemistry, such as drug discovery through computational techniques (virtual screening and virtual high throughput screening), drug repurposing, phenotypic screening assays, and employing classical medicinal chemistry, such as bioisosterism, metabolism-based drug design, and the discovery of new inhibitors through natural products, thereby presenting several promising compounds that may contain the advance of these pathogens.


Assuntos
Produtos Biológicos , Ebolavirus , Doença pelo Vírus Ebola , Animais , Ebolavirus/genética , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/epidemiologia , Química Farmacêutica , Descoberta de Drogas , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/química , Produtos Biológicos/farmacologia , RNA/farmacologia , RNA/uso terapêutico
7.
Naunyn Schmiedebergs Arch Pharmacol ; 395(3): 275-283, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35089406

RESUMO

Coronavirus disease 2019 (COVID-19) is a potentially fatal disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that preferentially infects the respiratory tract. Bradykinin (BK) is a hypotensive substance that recently emerged as one of the mechanisms to explain COVID-19-related complications. Concerning this, in this review, we try to address the complex link between BK and pathophysiology of COVID-19, investigating the role of this peptide as a potential target for pharmacological modulation in the management of SARS-CoV-2. The pathology of COVID-19 may be more a result of the BK storm than the cytokine storm, and which BK imbalance is a relevant factor in the respiratory disorders caused by SARS-CoV-2 infection. Regarding this, an interesting point of intervention for this disease is to modulate BK signaling. Some drugs, such as icatibant, ecallantide, and noscapine, and even a human monoclonal antibody, lanadelumab, have been studied for their potential utility in COVID-19 by modulating BK signaling. The interaction of the BK pathway and the involvement of cytokines such as IL-6 and IL1 may be key to the use of blockers, even if only as adjuvants. In fact, reduction of BK, mainly DABK, is considered a relevant strategy to improve clinical conditions of COVID-19 patients. In this context, despite the current unproven clinical efficacy, drugs repurposing that block B1 or B2 receptor activation have gained prominence for the treatment of COVID-19 in the world.


Assuntos
Bradicinina/antagonistas & inibidores , Tratamento Farmacológico da COVID-19 , SARS-CoV-2/efeitos dos fármacos , Bradicinina/fisiologia , COVID-19/etiologia , Reposicionamento de Medicamentos , Humanos , Interleucina-6/antagonistas & inibidores
8.
Phytother Res ; 35(7): 3769-3780, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33792975

RESUMO

Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. In spite of the increasing knowledge on molecular characteristics of different cancer types including CRC, there is limitation in the development of an effective treatment. The present study aimed to verify the antitumor effect of kopsanone, an indole alkaloid. To achieve this, we treated human colon cancer cells (Caco-2 and HCT-116) with kopsanone and analyzed its effects on cell viability, cell-cell adhesion, and actin cytoskeleton organization. In addition, functional assays including micronuclei formation, colony formation, cell migration, and invasiveness were performed. We observed that kopsanone reduced viability and proliferation and induced micronuclei formation of HCT-116 cells. Also, kopsanone inhibited anchorage-dependent colony formation and modulated adherens junctions (AJs), thus increasing the localization of E-cadherin and ß-catenin in the cytosol of the invasive cells. Finally, fluorescence assays showed that kopsanone decreased stress fibers formation and reduced migration but not invasion of HCT-116 cells. Taken together, these findings indicate that kopsanone reduces proliferation and migration of HCT-116 cells via modulation of AJs and can therefore be considered for future in vivo and clinical investigation as potential therapeutic agent for treatment of CRC.


Assuntos
Neoplasias do Colo , Alcaloides Indólicos/farmacologia , Células CACO-2 , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Células HCT116 , Humanos
9.
Curr Drug Targets ; 22(17): 1964-1985, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33858311

RESUMO

Bacterial resistance has become a major global concern, affecting about 500, 000 individuals in 22 countries. Thus, it is clear that Gram-negative bacteria have been receiving more attention in this scenario. These bacteria perform several resistance mechanisms, such as modifying lipid A from lipopolysaccharides as a product of the mcr-1 gene expression. This gene was initially identified in animals; however, it quickly spread to humans, spreading to 70 countries. Mcr-1 gene attributes resistance to polymyxin B and colistin, which are drugs established as the last alternative to combat Enterobacteriaceae bacteria. Notwithstanding the prevalence and lack of antibiotic therapies for such bacteria, this article aimed to compile information about natural compounds against the resistance attributed by this gene, including the activity of isolated colistin or its associations with other antibiotics. Among the studies that evaluated colistin's synergistic action with other compounds, azidothymidine and isoalantholactone stood out. On the other hand, the paenipeptin 1 analog showed satisfactory activities when associated with other antibiotics. Besides, it is worth mentioning that molecular docking results between ostole and eugenol toward phosphoethanolamine transferase MCR-1 revealed that these compounds could interact with critical amino acid residues for the catalytic action of this enzyme. Based on this, natural agents' role is evident against infections caused by mcr-1-positive bacteria, directly contributing to the development of new effective pharmacotherapies.


Assuntos
Produtos Biológicos , Colistina , Animais , Antibacterianos/farmacologia , Bactérias , Produtos Biológicos/farmacologia , Colistina/química , Colistina/farmacologia , Farmacorresistência Bacteriana , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Plasmídeos
10.
Curr Top Med Chem ; 21(21): 1900-1921, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33655860

RESUMO

Trypanosomatidae family belongs to the Kinetoplastida order, which consists of obligatory parasites that affect plants and all classes of vertebrates, especially humans and insects. Among the heteroxenic parasites, Leishmania spp., Trypanosoma cruzi, and T. brucei are protozoa of most significant interest for medicinal chemistry, being etiological agents of Leishmaniasis, Chagas, and Sleep Sickness diseases, respectively. Currently, inefficient pharmacotherapy, especially in chronic phases and low selectivity towards parasite/host cells, justifies the need to discover new drugs to treat them effectively. Among other targets, the sterol 14α-demethylase (CYP51), an enzyme responsible for ergosterol's biosynthesis in Trypanosomatidae parasites, has received more attention in the development of new bioactive compounds. In this context, antifungal ravuconazole proved to be the most promising drug among this class against T. cruzi, being used in combined therapy with Bnz in clinic trials. Non-antifungal inhibitors, such as VFV and VNF, have shown promising results against T. cruzi and T.brucei, respectively, being tested in Bnz-combined therapies. Among the experimental studies involving azoles, compound (15) was found to be the most promising derivative, displaying an IC50 value of 0.002 µM against amastigotes from T. cruzi, in addition to being non-toxic and highly selective towards TcCYP51 (< 25 nM). Interestingly, imidazole analog (16) was active against infectious forms of these three parasites, demonstrating Ki values of 0.17, 0.02, and 0.36 nM for CYP51 from T. cruzi, T. brucei, and L. infantum. Finally, this review will address promising inhibitors targeting sterol 14α-demethylase (CYP51) from Trypanosomatidae parasites, highlighting SAR studies, interactions with this target, and recent contributions and advances in the field, as well.


Assuntos
Inibidores de 14-alfa Desmetilase/farmacologia , Antiparasitários/farmacologia , Esterol 14-Desmetilase/metabolismo , Trypanosomatina/efeitos dos fármacos , Trypanosomatina/enzimologia , Inibidores de 14-alfa Desmetilase/química , Animais , Antiparasitários/química , Química Farmacêutica , Infecções por Euglenozoa/tratamento farmacológico , Infecções por Euglenozoa/parasitologia , Humanos
11.
Adv Pharm Bull ; 9(3): 432-438, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31592433

RESUMO

Purpose: Quercetin is a flavonoid known for its therapeutic properties and for forming complexes. Although the antimony-quercetin (SbQ) complex has been produced before, no previous exploration of its characteristics has been published in literature. Thus, this study aimed to characterize this complex, assess its stability and investigate its complexation site through its antibacterial activity. Methods: The SbQ complex was synthetized using Sb(III) potassium tartrate trihydrate and quercetin anhydrous (1:1) (v/v) as a solution and dried using three methods: rotaevaporation, lyophilization and spray drying. The material, in solution, was analyzed by UV-vis and fluorimetry; and, in the powder, by X-ray diffraction (XRD), both scanning electronic and fluorescence microscopy and infrared spectroscopy (FT-IR). Antimicrobial activity was evaluated via broth microdilution. Results: UV-vis exhibited a shoulder peak at 291 nm indicating metal chelation at C-ring of quercetin and confirmed 1:1 stoichiometry. Spectrofluorimetry showed an increase of intensity with the complex formation with an emission band (525 nm). After drying, XRD and SEM indicated loss of crystallinity and a difference in shape and size of the complex compared to its precursors. FT-IR suggested by a shift of frequency of the carbonyl group (1661 cm-1) that the quercetin bond to antimony by the C-3, followed by positions C-5 and C-4 carbonyl, which has been confirmed by MIC through the structure-activity relationship of the antibacterial activity of quercetin. Conclusion: These results provided a characterization of SbQ complex with the confirmation of its binding site, working as a guide for future studies involving this complex.

12.
Bioorg Med Chem ; 27(18): 3963-3978, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351847

RESUMO

Currently, more than 70 flaviviruses were identified and reported in the literature, whose Dengue (DENV), Zika (ZIKV), and West Nile (WNV) viruses have been responsible for millions of cases of infections worldwide, mainly in developing countries. These viruses are transmitted by the bite of mosquitoes from genus Aedes, or Culex and, in some cases, Stegomyia. Despite numerous efforts to identify a selective, safe, and effective antiviral agent, there is no currently approved drug for the treatment of flaviviral infections. Then, current pharmacological therapy has the objective to treat the clinical symptoms. Various peptidomimetics and peptide-derivatives have been synthesized and evaluated against several biological targets from flaviviruses with different applications, such as diagnosis, E protein inhibitors, entry inhibitors, virucidal inhibitors, and also viral replication inhibitors. Flaviviral replication depends on the NS3pro that is completely activated when it is complexed to its cofactor, NS2B; forming a viral enzymatic complex. The development of NS2B-NS3pro inhibitors is considered a challenging work due to its active site is shallow and open-pocket. In this work, we report all advances involving peptidomimetics, peptide-derived, and peptide-hybrids found in the literature. In sense, we discuss the influence of different functional groups in the activity and selectivity. Moreover, the first inhibitors reported in the literature as covalent ligands, comprising two basic residues followed by an electrophilic moiety that binds to the catalytic serine (Ser135-O-) are also discussed in details, such as trifluoromethyl ketones, aldehydes, and boronic acids. Furthermore, it is presented the influence of introducing transition metals, providing metallopeptide inhibitors; and cyclization of linear peptides, generating cyclic and macrocyclic peptide inhibitors. Finally, we provide the most accurate state of the art found in the literature, which can be utilized to design new and effective antiviral agents.


Assuntos
Dengue/tratamento farmacológico , Flavivirus/efeitos dos fármacos , Peptídeos/uso terapêutico , Inibidores de Proteases/uso terapêutico , Vírus do Nilo Ocidental/efeitos dos fármacos , Infecção por Zika virus/tratamento farmacológico , Humanos , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia
13.
Curr Top Med Chem ; 19(13): 1075-1091, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223089

RESUMO

BACKGROUND: Considering the need for the development of new antitumor drugs, associated with the great antitumor potential of thiophene and thiosemicarbazonic derivatives, in this work we promote molecular hybridization approach to synthesize new compounds with increased anticancer activity. OBJECTIVE: Investigate the antitumor activity and their likely mechanisms of action of a series of N-substituted 2-(5-nitro-thiophene)-thiosemicarbazone derivatives. METHODS: Methods were performed in vitro (cytotoxicity, cell cycle progression, morphological analysis, mitochondrial membrane potential evaluation and topoisomerase assay), spectroscopic (DNA interaction studies), and in silico studies (docking and molecular modelling). RESULTS: Most of the compounds presented significant inhibitory activity; the NCIH-292 cell line was the most resistant, and the HL-60 cell line was the most sensitive. The most promising compound was LNN-05 with IC50 values ranging from 0.5 to 1.9 µg.mL-1. The in vitro studies revealed that LNN-05 was able to depolarize (dose-dependently) the mitochondrial membrane, induceG1 phase cell cycle arrest noticeably, promote morphological cell changes associated with apoptosis in chronic human myelocytic leukaemia (K-562) cells, and presented no topoisomerase II inhibition. Spectroscopic UV-vis and molecular fluorescence studies showed that LNN compounds interact with ctDNA forming supramolecular complexes. Intercalation between nitrogenous bases was revealed through KI quenching and competitive ethidium bromide assays. Docking and Molecular Dynamics suggested that 5-nitro-thiophene-thiosemicarbazone compounds interact against the larger DNA groove, and corroborating the spectroscopic results, may assume an intercalating interaction mode. CONCLUSION: Our findings highlight 5-nitro-thiophene-thiosemicarbazone derivatives, especially LNN-05, as a promising new class of compounds for further studies to provide new anticancer therapies.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Nitrocompostos/farmacologia , Tiofenos/farmacologia , Tiossemicarbazonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Adulto , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Células Tumorais Cultivadas
14.
J Ethnopharmacol ; 242: 112037, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31247239

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: The leaves of Alpinia zerumbet is used in folk medicine in Brazil to treat hypertension. However, the cardioprotective effect of this plant has not been studied yet. AIM OF THIS STUDY: To evaluate the cardioprotective effects of the hydroalcoholic extract of the leaves of Alpinia zerumbet (AZE) against isoproterenol (ISO)-induced myocardial infarction in rats. MATERIAL AND METHODS: Rats were pretreated orally with AZE (300 mg/kg) for 30 days prior to ISO-induced myocardial infarction. The rats were sacrificed and hearts were collected and homogenized for biochemical analysis. At the end of the experiment, cardiac marker enzyme levels, histological and morphometric parameters, and hemodynamic measurements were assessed. Phytochemical compounds were verified by gas chromatography-mass spectrometry (GC-MS). RESULTS: Rats administered with ISO showed a significant increase in cardiac marker enzymes, i.e., in creatine kinase-NAC (CK-NAC) and CK-MB. Triphenyltetrazolium chloride (TTC) staining exhibited an increase in infarct areas. In the animals treated with ISO induced a significant increase in heart rate. Pretreatment with AZE significantly inhibited these effects of ISO. Moreover, biochemical findings were supported by histopathological observations. The GC-MS analyses of AZE identified volatile oils, kavalactones, and phytosterols. CONCLUSIONS: Haemodynamic, biochemical alteration and histopathological results suggest a cardioprotective protective effect of oral administration of AZE in isoproterenol induced cardiotoxicity.


Assuntos
Alpinia , Cardiotônicos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Creatina Quinase/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Isoproterenol , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Folhas de Planta , Ratos Wistar
15.
Biosens Bioelectron ; 133: 160-168, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30933710

RESUMO

An efficient and new electrochemical biosensor for detection of DNA damage, induced by the interaction of the hybrid anti-cancer compound (7ESTAC01) with DNA, was studied by differential pulse voltammetry (DPV). The biosensor consists of a Stem-Loop DNA (SL-DNA) probe covalently attached to the gold electrode (GE) surface that hybridizes to a complementary DNA strand (cDNA) to form a double-stranded DNA (dsDNA). The interaction and DNA damage induced by 7ESTAC01 was electrochemically studied based on the oxidation signals of the electroactive nucleic acids on the surface of the GE by DPV. As a result, the SL-DNA/GE and dsDNA/GE were tested with the reduced 7ESTAC01, showing the voltammetric signal of guanine and adenine, increase in the presence of 7ESTAC01. Under optimum conditions, the dsDNA/GE biosensor exhibited excellent DPV response in the presence of 7ESTAC01. The bonding interaction between 7ESTAC01 and calf thymus DNA (ctDNA) was confirmed by UV-Vis absorption spectroscopy, dynamic simulations (performed to investigate the DNA structure under physiological conditions), and molecular docking. Theoretical results showed the presence of hydrogen bonding and intercalation in the minor groove of DNA, involving hydrophobic interactions.


Assuntos
Antineoplásicos/química , Técnicas Biossensoriais , DNA/isolamento & purificação , Técnicas Eletroquímicas , Antineoplásicos/farmacologia , DNA/química , DNA/genética , Dano ao DNA/efeitos dos fármacos , DNA Complementar/química , DNA Complementar/genética , Ouro/química , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Sequências Repetidas Invertidas/genética , Simulação de Acoplamento Molecular , Oxirredução/efeitos dos fármacos , Raios Ultravioleta
16.
J Photochem Photobiol B ; 189: 165-175, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30366283

RESUMO

Acridines are considered an important class of compounds due to their wide variety of biological activities. In this work, we synthesized four acridine derivatives (1-4) and evaluated their biological activity against the Plasmodium falciparum W2 line, as well as studied the interaction with ctDNA and HSA using spectroscopic techniques and molecular docking. The acridine derivative 2 (IC50 = 0.90 ±â€¯0.08 µM) was more effective against P. falciparum than primaquine (IC50 = 1.70 ±â€¯0.10 µM) and similar to amsacrine (IC50 = 0.80 ±â€¯0.10 µM). In the fluorescence and UV-vis assays, it was verified that the acridine derivatives interact with ctDNA and HSA leading to a non-fluorescent supramolecular complex formation. The non-covalent binding constants ranged from 2.09 to 7.76 × 103 M-1, indicating moderate interaction with ctDNA. Through experiments with KI, fluorescence contact energy transfer and competition assays were possible to characterize the main non-covalent binding mode of the acridines evaluated with ctDNA as intercalation. The binding constants obtained showed a high linear correlation with the IC50 values against the antimalarial activity, suggesting that DNA may be the main biological target of these molecules. Finally, HSA interaction studies were performed and all evaluated compounds bind to the site II of the protein. The less active compounds (1 and 3) presented the highest affinity to HSA, indicating that the interaction with carrier protein can affect the (bio)availability of these compounds to the biological target.


Assuntos
Acridinas/síntese química , Antimaláricos/farmacologia , DNA/metabolismo , Albumina Sérica Humana/metabolismo , Acridinas/farmacologia , Sítios de Ligação , Humanos , Substâncias Intercalantes/farmacologia , Ligação Proteica , Relação Estrutura-Atividade
17.
Chem Biol Interact ; 280: 8-14, 2018 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-29208359

RESUMO

One of the promising fields for improving the effectiveness of antimicrobial agents is their combination with efflux pump inhibitors (EPIs), which besides expanding the use of existing antibiotics. The goal of this research was to evaluate a series of aminoguanidine hydrazones (AGH's, 1-19) as antibacterial agents and NorA efflux pump inhibitors in Staphylococcus aureus strain SA-1199B. Molecular modeling and docking studies were also performed in order to explain at the molecular level the interactions of the compounds with the generated NorA efflux pump model. The MICs of the antibiotic and ethidium bromide were determined by microdilution assay in absence or presence of a subinhibitory concentration of aminoguanidine hydrazones and macrophages viability was determined through MTT assay. Bioinformatic software Swiss-Model and AutoDock 4.2 were used to perform modeling and docking studies, respectively. As results, all AGH's were able to potentiate the action for the antibiotic norfloxacin, causing MIC's reduction of 16-fold and 32-fold to ethidium bromide. In the cell viability test, the concentration of 10 µg/mL showed better results than 90% and the concentration of 1000 µg/mL showed the lowest viability, reaching a maximum of 50% for the analyzed aminoguanidine hydrazones. Molecular docking studies showed that both norfloxacin and derivative 13 were recognized by the same binding site of NorA pump, suggesting a competitive mechanism. The present work demonstrated for the first time that AGH derivatives have potential to be putative inhibitors of NorA efflux pump, showing a promising activity as an antibacterial drug development.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hidrazonas/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Staphylococcus aureus/metabolismo , Animais , Proteínas de Bactérias/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Guanidinas/química , Hidrazonas/síntese química , Hidrazonas/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Norfloxacino/farmacologia , Estrutura Terciária de Proteína , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
18.
Curr Comput Aided Drug Des ; 14(1): 68-78, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28523999

RESUMO

BACKGROUND: Chagas' disease is one of the main causes of heart failure in developing countries. The disadvantages of current therapy include the undesirable side-effects, resistance, and therapeutic adhesion. The development of new efficient and safe drugs is, therefore, an issue of extreme importance. OBJECTIVES: In order to gain a better understanding of how the compounds interact with the target, computational methods are essential. METHODS: In this theoretical study, we report a docking protocol applied to a dataset of 173 cruzain inhibitors with IC50 values of less than 10 µM, belonging 16 different chemical classes. A preliminary analysis was performed, where the best protein structure for the study was identified. RESULTS: The enzyme was validated by redocking and a fingerprint graph for the ligand-enzyme interactions was generated, allowing the identification of the main amino acid residues related to the activity. Additionally, a larger cluster was generated, allowing the visualization of the orientation of the compounds and providing binding information for the different classes of compounds as well as their interaction in the cruzain active site. Amino acid residues other than those known as the catalytic triad (Gly23, Cys25, and Gly65) were identified, for example, Gln19 and Asp158. CONCLUSION: This provides a better insight into the mode of interaction of various cruzain inhibitors, which show IC50 values in the nanomolar range but which do not interact with the triad. These findings can help researchers to find new cruzain inhibitors for use in the fight against the Chagas disease.


Assuntos
Cisteína Endopeptidases/química , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Proteínas de Protozoários/química , Ligação Proteica
19.
Chemistry ; 23(55): 13676-13683, 2017 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-28696045

RESUMO

A simple, sustainable, efficient, mild, and low-cost protocol was developed for d-glucose-assisted Cu-catalyzed Ullmann reactions in water for amides, carbamates, and nitrogen-containing heterocycles. The reaction was compatible with diverse aryl/heteroaryl iodides, giving highly substituted pyridine, indole, or indazole rings. This method offers an attractive alternative to existing protocols, because the reaction proceeds in aqueous media, occurs at or near ambient temperature, and provides the N-arylated products in good to high yields.

20.
ScientificWorldJournal ; 2015: 751791, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26146655

RESUMO

INTRODUCTION: Surgical site infection remains a challenge for hospital infection control, especially when it relates to skin antisepsis in the surgical site. OBJECTIVE: To analyze the antimicrobial activity in vivo of an antiseptic from ethanol crude extracts of P. granatum and E. uniflora against Gram-positive and Gram-negative bacteria. METHODS: Agar drilling and minimal inhibitory tests were conducted for in vitro evaluation. In the in vivo bioassay were used Wistar rats and Staphylococcus aureus (ATCC 25923) and Staphylococcus epidermidis (ATCC 14990). Statistical analysis was performed through variance analysis and Scott-Knott cluster test at 5% probability and significance level. RESULTS: In the in vitro, ethanolic extracts of Punica granatum and Eugenia uniflora and their combination showed the best antimicrobial potential against S. epidermidis and S. aureus. In the in vivo bioassay against S. epidermidis, there was no statistically significant difference between the tested product and the patterns used after five minutes of applying the product. CONCLUSION: The results indicate that the originated product is an antiseptic alternative source against S. epidermidis compared to chlorhexidine gluconate. It is suggested that further researches are to be conducted in different concentrations of the test product, evaluating its effectiveness and operational costs.


Assuntos
Antibacterianos/farmacologia , Lythraceae/química , Extratos Vegetais/farmacologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Modelos Animais de Doenças , Feminino , Testes de Sensibilidade Microbiana , Extratos Vegetais/administração & dosagem , Ratos , Infecções Estafilocócicas/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA