RESUMO
Cenotes are habitats with unique physical, chemical, and biological features. Unexplored microorganisms from these sinkholes represent a potential source of bioactive molecules. Thus, a series of cultivable fungi (Aspergillus spp. NCA257, NCA264, and NCA276, Stachybotrys sp. NCA252, and Cladosporium sp. NCA273) isolated from the cenote Tza Itzá were subjected to chemical, coculture, and metabolomic analyses. Nineteen compounds were obtained and tested for their antimicrobial potential against ESKAPE pathogens, Mycobacterium tuberculosis, and nontuberculous mycobacteria. In particular, phenylspirodrimanes from Stachybotrys sp. NCA252 showed significant activity against MRSA, MSSA, and mycobacterial strains. On the other hand, the absolute configuration of the new compound 17-deoxy-aspergillin PZ (1) isolated from Aspergillus sp. NCA276 was established via single-crystal X-ray crystallography. Also, the chemical analysis of the cocultures between Aspergillus and Cladosporium strains revealed the production of metabolites that were not present or were barely detected in the monocultures. Finally, molecular networking analysis of the LC-MS-MS/MS data for each fungus was used as a tool for the annotation of additional compounds, increasing the chemical knowledge on the corresponding fungal strains. Overall, this is the first systematic chemical study on fungi isolated from a sinkhole in Mexico.
RESUMO
Chemical investigation of Punctularia atropurpurascens strain HM1 (Punctulariaceae), a corticioid isolated from a decorticated piece of Quercus bark collected in Bosque de Tlalpan, Mexico City, led to the isolation of a new drimane, 1-α-hydroxy-isodrimenine (1: ) and a new tetrahydroxy kauranol, 16-hydroxy-phlebia-nor-kauranol (2: ), together with the known N-phenylacetamide (3: ). Structures of all compounds were elucidated by spectroscopic and spectrometric methods, and the absolute configuration of 1: and 2: was confirmed via single-crystal X-ray crystallography. The isolated compounds showed modest antimycobacterial activity.
Assuntos
Basidiomycota , Terpenos , Antibacterianos/farmacologia , Cristalografia por Raios X , Fungos , Estrutura Molecular , Terpenos/farmacologiaRESUMO
A collection of 29 cultivable fungal strains isolated from deep-sea sediments of the Gulf of Mexico were cultivated under the "one strain, many compounds" approach to explore their chemical diversity and antimicrobial potential. From the 87 extracts tested, over 50% showed antimicrobial activity, and the most active ones were those from cultures grown at 4 °C in darkness for 60 days (resembling deep-sea temperature). PCA analysis of the LC-MS data of all the extracts confirmed that culture temperature is the primary factor in the variation of the 4462 metabolite features, accounting for 21.3% of the variation. The bioactivity-guided and conventional chemical studies of selected fungal strains allowed the identification of several active and specialized metabolites. Finally, metabolomics analysis by GNPS molecular networking and manual dereplication revealed the biosynthetic potential of these species to produce interesting chemistry. This work uncovers the chemical and biological study of marine-derived fungal strains from deep-sea sediments of the Gulf of Mexico.
Assuntos
Anti-Infecciosos/química , Fungos/química , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Fungos/metabolismo , Sedimentos Geológicos/microbiologia , Golfo do México , MetabolomaRESUMO
BACKGROUND: Tuberculosis (TB) has been a challenging disease worldwide, especially for the neglected poor populations. Presently, there are approximately 2 billion people infected with TB worldwide and 10 million people in the world fell ill with active TB, leading to 1.5 million deaths. INTRODUCTION: The classic treatment is extensive and the drug- and multi-drug resistance of Mycobacterium tuberculosis has been a threat to the efficacy of the drugs currently used. Therefore, the rational design of new anti-TB candidates is urgently needed. METHODS: With the aim of contributing to face this challenge, 78 compounds have been proposed based on SBDD (Structure-Based Drug Design) strategies applied to target the M. tuberculosis phosphopantetheine adenylyltransferase (MtPPAT) enzyme. Ligand-Based Drug Design (LBDD) strategies were also used for establishing Structure-Activity Relationships (SAR) and for optimizing the structures. MtPPAT is important for the biosynthesis of coenzyme A (CoA) and it has been studied recently toward the discovery of new inhibitors. RESULTS: After docking simulations and enthalpy calculations, the interaction of selected compounds with MtPPAT was found to be energetically favorable. The most promising compounds were then synthesized and submitted to anti-M. tuberculosis and MtPPAT inhibition assays. CONCLUSION: One of the compounds synthesized (MCP163), showed the highest activity in both of these assays.
Assuntos
Antituberculosos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nucleotidiltransferases/antagonistas & inibidores , Antituberculosos/síntese química , Antituberculosos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Nucleotidiltransferases/metabolismoRESUMO
Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di-N-oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-di-N-oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds (T-007, T-018, T-011, T-069, T-070, T-072, T-085 and T-088) had an activity similar to that of the reference drug isoniazid (minimum inhibitory concentration (MIC) = 0.12 µg/mL) with an effect on nonreplicative cells and drug monoresistant strains. Structural activity relationship analysis showed that the steric effect of an ester group at 7-position is key to enhancing its biological effects. Additionally, T-069 showed a high stability after 24 h in human plasma at 37 °C.
Assuntos
Antituberculosos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Quinoxalinas/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Cromatografia Líquida , Farmacorresistência Bacteriana/efeitos dos fármacos , Estabilidade de Medicamentos , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Espectrometria de Massas em TandemRESUMO
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 µM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Óxidos/química , Análise Espectral/métodosRESUMO
Fractionation of the bioactive CHCl3-MeOH (1:1) extracts obtained from two collections of the sponge consortium Plakortis symbiotica-Xestospongia deweerdtae from Puerto Rico provided two new plakinidone analogues, designated as plakinidone B (2) and plakinidone C (3), as well as the known plakinidone (1), plakortolide F (4), and smenothiazole A (5). The structures of 1-5 were characterized on the basis of 1D and 2D NMR spectroscopic, IR, UV, and HRMS analysis. The absolute configurations of plakinidones 2 and 3 were established through chemical correlation methods, VCD/ECD experiments, and spectroscopic data comparisons. When assayed in vitro against Mycobacterium tuberculosis H37Rv, none of the plakinidones 1-3 displayed significant activity, whereas smenothiazole A (5) was the most active compound, exhibiting an MIC value of 4.1 µg/mL. Synthesis and subsequent biological screening of 8, a dechlorinated version of smenothiazole A, revealed that the chlorine atom in 5 is indispensable for anti-TB activity.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/química , Peróxidos/farmacologia , Plakortis/química , Tiazóis/síntese química , Tiazóis/farmacologia , Valina/análogos & derivados , Xestospongia/química , Animais , Antituberculosos/síntese química , Antituberculosos/química , Produtos Biológicos , Dioxinas/síntese química , Dioxinas/química , Dioxinas/farmacologia , Lactonas/síntese química , Lactonas/química , Lactonas/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Mycobacterium tuberculosis/metabolismo , Peróxidos/síntese química , Peróxidos/química , Porto Rico , Tiazóis/química , Valina/síntese química , Valina/química , Valina/farmacologiaRESUMO
New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17-20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 µM and <10 µM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11-545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents.
Assuntos
Antituberculosos/farmacologia , Chalcona/farmacologia , Descoberta de Drogas , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Antituberculosos/síntese química , Antituberculosos/química , Chalcona/síntese química , Chalcona/química , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células VeroRESUMO
Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2-10.98µM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50µM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones.
Assuntos
Antiprotozoários/farmacologia , Chalconas/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Leishmania infantum/efeitos dos fármacos , Nitrofuranos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Anfotericina B/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Chalconas/síntese química , Chalconas/química , Chlorocebus aethiops , Simulação por Computador , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Bases de Dados Factuais , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Nitrofuranos/síntese química , Nitrofuranos/química , Piperazinas/síntese química , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Células VeroRESUMO
Although infections with NonTuberculous Mycobacteria have become less common in AIDS patients, they are important opportunistic infections after surgical procedures, likely because they are ubiquitous and not efficiently killed by many commonly used disinfectants. In Venezuela there have recently been many non-tuberculous mycobacteria soft tissue infections after minor surgical procedures, some apparently related to the use of a commercial disinfectant based on a Quaternary Ammonium Compound. We studied the activity of this and other quaternary ammonium compounds on different non-tuberculous mycobacteria by transforming the mycobacteria with a dnaA-gfp fusion and then monitoring fluorescence to gauge the capacity of different quaternary ammonium compounds to inhibit bacterial growth. The minimum inhibitory concentration varied for the different quaternary ammonium compounds, but M. chelonae and M. abscessus were consistently more resistant than M. smegmatis, and M. terrae more resistant than M. bovis BCG.(AU)
Assuntos
Humanos , Micobactérias não Tuberculosas/crescimento & desenvolvimento , Compostos de Amônio Quaternário , Desinfestantes , Antibacterianos , Corantes Fluorescentes , Síndrome da Imunodeficiência AdquiridaRESUMO
Abstract Although infections with NonTuberculous Mycobacteria have become less common in AIDS patients, they are important opportunistic infections after surgical procedures, likely because they are ubiquitous and not efficiently killed by many commonly used disinfectants. In Venezuela there have recently been many non-tuberculous mycobacteria soft tissue infections after minor surgical procedures, some apparently related to the use of a commercial disinfectant based on a Quaternary Ammonium Compound. We studied the activity of this and other quaternary ammonium compounds on different non-tuberculous mycobacteria by transforming the mycobacteria with a dnaA-gfp fusion and then monitoring fluorescence to gauge the capacity of different quaternary ammonium compounds to inhibit bacterial growth. The minimum inhibitory concentration varied for the different quaternary ammonium compounds, but M. chelonae and M. abscessus were consistently more resistant than M. smegmatis, and M. terrae more resistant than M. bovis BCG.
Assuntos
Expressão Gênica , Proteínas de Fluorescência Verde , Desinfetantes/farmacologia , Compostos de Amônio Quaternário/farmacologia , Antibacterianos/farmacologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Plasmídeos/genética , Proteínas Recombinantes de Fusão/genética , Testes de Sensibilidade Microbiana , Proteínas de Fluorescência Verde/genética , Relação Dose-Resposta a Droga , Micobactérias não Tuberculosas/classificação , Micobactérias não Tuberculosas/genéticaRESUMO
Although infections with NonTuberculous Mycobacteria have become less common in AIDS patients, they are important opportunistic infections after surgical procedures, likely because they are ubiquitous and not efficiently killed by many commonly used disinfectants. In Venezuela there have recently been many non-tuberculous mycobacteria soft tissue infections after minor surgical procedures, some apparently related to the use of a commercial disinfectant based on a Quaternary Ammonium Compound. We studied the activity of this and other quaternary ammonium compounds on different non-tuberculous mycobacteria by transforming the mycobacteria with a dnaA-gfp fusion and then monitoring fluorescence to gauge the capacity of different quaternary ammonium compounds to inhibit bacterial growth. The minimum inhibitory concentration varied for the different quaternary ammonium compounds, but M. chelonae and M. abscessus were consistently more resistant than M. smegmatis, and M. terrae more resistant than M. bovis BCG.
Assuntos
Antibacterianos/farmacologia , Desinfetantes/farmacologia , Expressão Gênica , Proteínas de Fluorescência Verde , Micobactérias não Tuberculosas/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Relação Dose-Resposta a Droga , Proteínas de Fluorescência Verde/genética , Testes de Sensibilidade Microbiana , Micobactérias não Tuberculosas/classificação , Micobactérias não Tuberculosas/genética , Plasmídeos/genética , Proteínas Recombinantes de Fusão/genéticaRESUMO
Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile.
Assuntos
Antituberculosos/farmacologia , Ésteres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pirazinamida/análogos & derivados , Animais , Antituberculosos/síntese química , Antituberculosos/toxicidade , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/toxicidade , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , Pirazinamida/síntese química , Pirazinamida/farmacologia , Pirazinamida/toxicidade , Relação Estrutura-Atividade , Células VeroRESUMO
Compounds such as triclosan, diclofenac and trimetropin posses antibacterial activity, including mycobacterial; their structures are based on two aromatic rings joined by a methylene or a heteroatom. Since a similar structural system is found in natural diarylfuran- based lignans, we studied plants known with this type of lignans, as potential active against Mycobacterium tuberculosis. Fractions of the active extracts were tested for anti-TB activity and their chemical constituents analyzed by NMR spectroscopy. Several extracts and chromatographical fractions exhibited > 90 percent inhibition of M. tuberculosis at 128 ug/mL. Methylpluviatilol, a pure compound isolated from Virola sebifera, was active at this concentration.. These findings suggest that plant species of the families here studied may yield novel lead compounds for the development of antimycobacterial agents.
Compuestos tales como triclosan, diclofenac y trimetoprim poseen actividad antibacterial, incluyendo la antimicobacterial; sus estructuras están basadas en dos anillos aromáticos unidos por un metileno o un heteroátomo. Debido a que en la naturaleza se encuentra un sistema estructural similar del tipo diarilfurano en los lignanos, así como otros subtipos, nosotros estudiamos plantas contra Mycobacterium tuberculosis, de las que se sabe contienen lignanos Las fracciones cromatográficas de los extractos activos fueron ensayadas para actividad anti.Tb y sus constituyentes químicos se analizaron por espectroscopía de RMN. Varios extractos y fracciones cromatográficas exhibieron una inhibición superior al 90 por ciento a 128 ug/mL; el compuesto metilpluviatilol, aislado de mostró una inhibición del 99 por ciento a esa concentración. Esos hechos sugieren que las especies de plantas de las familias aquí estudiadas podrían suministrar nuevos compuestos líderes para el desarrollo de agentes antimicobacteriales.
Assuntos
Antibacterianos/farmacologia , Furanos/farmacologia , Lignanas/farmacologia , Mycobacterium tuberculosis , Bioensaio , Espectroscopia de Ressonância MagnéticaRESUMO
Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity.
Assuntos
Antituberculosos/farmacologia , Complexos de Coordenação/farmacologia , Iminas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Fosfinas/farmacologia , Ácidos Picolínicos/farmacologia , Rutênio/farmacologia , Animais , Antituberculosos/efeitos adversos , Antituberculosos/síntese química , Antituberculosos/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Feminino , Humanos , Iminas/síntese química , Iminas/química , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/isolamento & purificação , Fosfinas/síntese química , Fosfinas/química , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Rutênio/química , Testes de Toxicidade AgudaRESUMO
TB is a global public health emergency in which new drugs are desperately needed. Herein we report on the synthesis of a diverse panel of 41 aryl allylic azides, thiocyanates, isothiouronium salts, and N,N'-diacetylisothioureas that were evaluated for their in vitro activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb) H(37)Rv and toxicity to VERO cells. We found a selective group of new and promising compounds having good (micromolar) to excellent (sub-micromolar) potency against replicating Mtb H(37)Rv. Allylic thiocyanates bearing halophenyl (halo=2-Br, 4-Br, 4-Cl, 4-F), 4-methylphenyl and 2-naphthyl moieties were the most active as antitubercular agents. In particular, the 2-bromophenyl-substituted thiocyanate showed MIC=0.25 µM against replicating Mtb, MIC=8.0 µM against non-replicating Mtb and IC(50)=32 µM in the VERO cellular toxicity assay.
Assuntos
Compostos Alílicos/química , Compostos Alílicos/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiocianatos/química , Tiocianatos/farmacologia , Tuberculose/tratamento farmacológico , Compostos Alílicos/toxicidade , Animais , Antituberculosos/toxicidade , Chlorocebus aethiops , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tiocianatos/toxicidade , Tuberculose/microbiologia , Células VeroRESUMO
This paper describes the synthesis and characterization of four new ruthenium complexes containing 1,4 bis(diphenylphosphino)butane (dppb), 2-pyridinecarboxylic acid anion (pic) and the diimines [(2,2'-bipyridine (bipy), 4,4'-dimethyl-2,2'-bipyridine (Me-bipy), 4,4'-dichloro-2,2'-bipyridine (Cl-bipy) and 1,10-phenanthroline (phen) as ligands, with formulae [Ru(pic)(dppb)(bipy)]PF(6) (SCAR01), [Ru(pic)(dppb)(Me-bipy)]PF(6) (SCAR02), [Ru(pic)(dppb)(Cl-bipy)]PF(6) (SCAR03) and [Ru(pic)(dppb)(phen)]PF(6) (SCAR04). Additionally, the in vitro anti-Mycobacterium tuberculosis (MTB) activity, cytotoxicity and activity against in vitro infection of these complexes and two more complexes, cis-[Ru(pic)(dppe)(2)]PF(6) (SCAR05) and cis-[RuCl(2)(dppb)(bipy)] (SCAR06), and their free ligands are described and discussed. All compounds showed excellent MIC against MTB, low cytotoxicity and a selectivity index higher than 10. Also, all compounds showed significant intracellular inhibition and the compound SCAR05 showed a better activity than rifampin and SQ109. This is the first report of activity against in vitro infection of ruthenium compounds.
Assuntos
Antituberculosos/farmacologia , Iminas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Fosfinas/farmacologia , Ácidos Picolínicos/farmacologia , Rutênio/farmacologia , Animais , Antituberculosos/química , Linhagem Celular , Cristalografia por Raios X , Humanos , Iminas/química , Camundongos , Modelos Moleculares , Compostos Organometálicos/farmacologia , Fosfinas/química , Ácidos Picolínicos/química , Rutênio/química , Tuberculose/tratamento farmacológicoRESUMO
The aim of this study was to identify a candidate drug for the development of anti-tuberculosis therapy from previously synthesized compounds based on the thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones compounds. The minimal inhibitory concentration (MIC) of these compounds against Mycobacterium tuberculosis was determined. Their in vitro cytotoxicity to J774 cells (IC50) was determined to establish a selectivity index (SI) (SI=IC50/MIC). The best compounds were the thiosemicarbazones (2, 3 and 4) and the hydrazide/hydrazones (14, 15, 16 and 18). The results are comparable to or better than those of "first line" or "second line" drugs commonly used to treat TB, suggesting these compounds as anti-TB drug candidates.
Assuntos
Antituberculosos/farmacologia , Hidrazinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Semicarbazonas/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Hidrazinas/síntese química , Hidrazinas/química , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/metabolismo , Semicarbazonas/síntese química , Semicarbazonas/química , Relação Estrutura-AtividadeRESUMO
The synthesis, characterization and the anti-Mycobacterium tuberculosis (MTB) activities of three ruthenium complexes containing the 2-pyridinecarboxylic acid anion (picolinate), with formulae cis- [Ru(pic)(dppm)(2)]PF(6) (1), cis- [Ru(pic)(dppe)(2)]PF(6) (2) and [Ru(pic)(2)(PPh(3))(2)] (3) [pic=2-pyridinecarboxylate; dppm=bis(diphenylphosphino)methane; dppe=1,2-bis(diphenylphosphino)ethane; PPh(3)=triphenylphosphine] are reported in this article. The complexes were characterized by elemental analysis, spectroscopic and electrochemical techniques. Their in vitro antimycobacterial activity was determinated as the Minimum Inhibitory Concentration (MIC) for MTB cell growth, measured by the REMA method. The best MICs were found for complexes (1) and (2), with values of 0.78 and 0.26 microg/mL, respectively. The results are comparable to or better than "first line" or "second line" drugs commonly used in the treatment of TB.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fosfinas/química , Ácidos Picolínicos/química , Rutênio/química , Antibacterianos/síntese química , Eletroquímica , Elétrons , Ligantes , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Compostos Organometálicos/síntese químicaRESUMO
A series of 3beta-hydroxy steroid analogues possessing a contracted cyclopentane B-ring were prepared based on the initial activity screening of a recently reported naturally occurring marine 5(6-->7)abeo-sterol against Mycobacterium tuberculosis. All of the novel ring B abeo-sterols synthesized showed good inhibitory activity, whereas none of the starting steroids based on the common 3beta-hydroxy-Delta(5)-cholestane nucleus, proved to be active. Therefore, the 5(6-->7)abeo-sterol nucleus present in compounds 3, 5, 7, 9, and 11 represents a novel scaffold for the development of new antitubercular agents.