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1.
J Antibiot (Tokyo) ; 75(9): 483-490, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35882958

RESUMO

Amycolatopsis sp. MST-135876 was isolated from soil collected from the riverbank of El Pont de Suert, Catalonia, Spain. Cultivation of MST-135876 on a range of media led to the discovery of a previously unreported dichlorinated cyclic hexapeptide, suertide A (D-Ser, 5-Cl-D-Trp, 6-Cl-D-Trp, L-Ile, D-Val, D-Glu), featuring an unprecedented pair of adjacent 5/6-chlorotryptophan residues. Supplementing the growth medium with KBr resulted in production of the mono- and dibrominated analogues suertides B and C, respectively. Suertides A-C displayed selective activity against Bacillus subtilis (MIC 1.6 µg ml-1) and Staphylococcus aureus (MIC 3.1, 6.3, and 12.5 µg ml-1, respectively), while suertides A and B showed appreciable activity against methicillin-resistant S. aureus (MIC 1.6 and 6.3 µg ml-1, respectively).


Assuntos
Amycolatopsis , Staphylococcus aureus Resistente à Meticilina , Antibacterianos/química , Testes de Sensibilidade Microbiana , Staphylococcus aureus
2.
Molecules ; 27(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164153

RESUMO

The Streptomyces genus has been a rich source of bioactive natural products, medicinal chemicals, and novel drug leads for three-quarters of a century. Yet studies suggest that the genus is capable of making some 150,000 more bioactive compounds than all Streptomyces secondary metabolites reported to date. Researchers around the world continue to explore this enormous potential using a range of strategies including modification of culture conditions, bioinformatics and genome mining, heterologous expression, and other approaches to cryptic biosynthetic gene cluster activation. Our survey of the recent literature, with a particular focus on the year 2020, brings together more than 70 novel secondary metabolites from Streptomyces species, which are discussed in this review. This diverse array includes cyclic and linear peptides, peptide derivatives, polyketides, terpenoids, polyaromatics, macrocycles, and furans, the isolation, chemical structures, and bioactivity of which are appraised. The discovery of these many different compounds demonstrates the continued potential of Streptomyces as a source of new and interesting natural products and contributes further important pieces to the mostly unfinished puzzle of Earth's myriad microbes and their multifaceted chemical output.


Assuntos
Metabolismo Secundário , Streptomyces/metabolismo , Macrolídeos/metabolismo , Família Multigênica , Peptídeos/genética , Peptídeos/metabolismo , Policetídeos/metabolismo , Streptomyces/genética , Terpenos/metabolismo
3.
J Antibiot (Tokyo) ; 75(2): 108-112, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34880415

RESUMO

Streptomyces sp. MST-91080 was isolated from a soil sample collected in Queensland, Australia. From this strain, yeppoonic acids A - D were purified and spectroscopically characterised. The yeppoonic acids are a family of diene enecarboxylic acids on a 1,2,4-trisubstituted benzene scaffold, structurally related to other Streptomyces secondary metabolites MF-EA-705α/ß, NFAT-133 and the lorneic acids. Yeppoonic acids B and C show strong cytotoxicity against the NS-1 mouse myeloma cell line (IC50 2.3 µg ml-1 and 3.8 µg ml-1, respectively) and moderate activity against the DU 145 human prostate cancer cell line (IC50 32.8 µg ml-1 and 49.6 µg ml-1, respectively).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Streptomyces/metabolismo , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Austrália , Ácidos Carboxílicos , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Oxazóis/química , Oxazóis/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Queensland , Microbiologia do Solo , Streptomyces/química
4.
Dalton Trans ; 50(11): 3931-3942, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33635937

RESUMO

The coordination chemistry of N-functionalised cyclam ligands has a rich history, yet cyclam derivatives with pendant alkynes are largely unexplored. This is despite the significant potential and burgeoning application of N-propargyl cyclams and related compounds in the creation of diversely functionalised cyclam derivatives via copper-catalysed azide-alkyne 'click' reactions. Herein we describe single crystal X-ray diffraction and spectroscopic investigations of the coordination chemistry of copper(ii) complexes of cyclam derivatives with between 1 and 4 pendant alkynes. The crystal structures of these copper complexes unexpectedly reveal a range of coordination modes, and the surprising occurrence of five unique complexes within a single recrystallisation of the tetra-N-propargyl cyclam ligand. One of these species exhibits weak intramolecular copper-alkyne coordination, and another is formed by a surprising intramolecular copper-mediated hydroalkoxylation reaction with the solvent methanol, transforming one of the pendant alkynes to an enol ether. Multiple functionalisation of the tetra-N-propargyl ligand is demonstrated via a 'tetra-click' reaction with benzyl azide, and the copper-binding behaviour of the resulting tetra-triazole ligand is characterised spectroscopically.

5.
Chembiochem ; 22(10): 1687-1705, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33415840

RESUMO

Isopenicillin N synthase (IPNS) is a non-heme iron oxidase (NHIO) that catalyses the cyclisation of tripeptide δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to bicyclic isopenicillin N (IPN). Over the last 25 years, crystallography has shed considerable light on the mechanism of IPNS catalysis. The first crystal structure, for apo-IPNS with Mn bound in place of Fe at the active site, reported in 1995, was also the first structure for a member of the wider NHIO family. This was followed by the anaerobic enzyme-substrate complex IPNS-Fe-ACV (1997), this complex plus nitric oxide as a surrogate for co-substrate dioxygen (1997), and an enzyme product complex (1999). Since then, crystallography has been used to probe many aspects of the IPNS reaction mechanism, by crystallising the protein with a diversity of substrate analogues and triggering the oxidative reaction by using elevated oxygen pressures to force the gaseous co-substrate throughout protein crystals and maximise synchronicity of turnover in crystallo. In this way, X-ray structures have been elucidated for a range of complexes closely related to and/or directly derived from key intermediates in the catalytic cycle, thereby answering numerous mechanistic questions that had arisen from solution-phase experiments, and posing many new ones. The results of these crystallographic studies have, in turn, informed computational experiments that have brought further insight. These combined crystallographic and computational investigations augment and extend the results of earlier spectroscopic analyses and solution phase studies of IPNS turnover, to enrich our understanding of this important protein and the wider NHIO enzyme family.


Assuntos
Oxirredutases/química , Aspergillus/enzimologia , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Compostos Ferrosos/química , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Simulação de Dinâmica Molecular , Oxirredutases/genética , Oxirredutases/metabolismo , Penicilinas/química , Penicilinas/metabolismo , Especificidade por Substrato
6.
J Org Chem ; 85(21): 13438-13452, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-32786609

RESUMO

We have discovered and studied a tele-substitution reaction in a biologically important heterocyclic ring system. Conditions that favor the tele-substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base or the use of softer nucleophiles, less polar solvents, and larger halogens on the electrophile. Using results from X-ray crystallographic and isotope labeling experiments, a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active antiplasmodium compounds of Series 4 of the Open Source Malaria consortium.


Assuntos
Antimaláricos , Antimaláricos/farmacologia , Halogênios , Pirazinas , Solventes
7.
J Antibiot (Tokyo) ; 73(11): 756-765, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32555501

RESUMO

Chemical investigation of a previously unreported indigenous Australian Streptomyces strain MST-91080 has identified six novel analogues related to the oxazole-pendanted macrodiolide, conglobatin. Phylogenetic analysis of the 16S rRNA gene sequence identified MST-91080 as a species of Streptomyces, distinct from reported conglobatin producer, Streptomyces conglobatus ATCC 31005. Conglobatins B-E diverge from conglobatin through differing patterns of methylation on the macrodiolide skeleton. The altered methyl positions suggest a deviation from the published biosynthetic pathway, which proposed three successive methylmalonyl-CoA extender unit additions to the conglobatin monomer. Conglobatins B1, C1 and C2 exhibited more potent cytotoxic activity selectively against the NS-1 myeloma cell line (IC50 0.084, 1.05 and 0.45 µg ml-1, respectively) compared with conglobatin (IC50 1.39 µg ml-1).


Assuntos
Citotoxinas/isolamento & purificação , Oxazóis/isolamento & purificação , Linhagem Celular Tumoral/efeitos dos fármacos , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxazóis/química , Streptomyces/química
8.
Chem Sci ; 11(10): 2627-2639, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32206266

RESUMO

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.

10.
Beilstein J Org Chem ; 15: 2631-2643, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31807198

RESUMO

Chemical investigation of an undescribed Australian fungus, Aspergillus nanangensis, led to the identification of the nanangenines - a family of seven new and three previously reported drimane sesquiterpenoids. The structures of the nanangenines were elucidated by detailed spectroscopic analysis supported by single crystal X-ray diffraction studies. The compounds were assayed for in vitro activity against bacteria, fungi, mammalian cells and plants. Bioinformatics analysis, including comparative analysis with other acyl drimenol-producing Aspergilli, led to the identification of a putative nanangenine biosynthetic gene cluster that corresponds to the proposed biosynthetic pathway for nanangenines.

11.
Sci Rep ; 9(1): 14396, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591407

RESUMO

Mycobacterium tuberculosis infects over 10 million people annually and kills more people each year than any other human pathogen. The current tuberculosis (TB) vaccine is only partially effective in preventing infection, while current TB treatment is problematic in terms of length, complexity and patient compliance. There is an urgent need for new drugs to combat the burden of TB disease and the natural environment has re-emerged as a rich source of bioactive molecules for development of lead compounds. In this study, one species of marine sponge from the Tedania genus was found to yield samples with exceptionally potent activity against M. tuberculosis. Bioassay-guided fractionation identified bengamide B as the active component, which displayed activity in the nanomolar range against both drug-sensitive and drug-resistant M. tuberculosis. The active compound inhibited in vitro activity of M. tuberculosis MetAP1c protein, suggesting the potent inhibitory action may be due to interference with methionine aminopeptidase activity. Tedania-derived bengamide B was non-toxic against human cell lines, synergised with rifampicin for in vitro inhibition of bacterial growth and reduced intracellular replication of M. tuberculosis. Thus, bengamides isolated from Tedania sp. show significant potential as a new class of compounds for the treatment of drug-resistant M. tuberculosis.


Assuntos
Antituberculosos/farmacologia , Azepinas/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/química , Azepinas/química , Interações Medicamentosas , Testes de Sensibilidade Microbiana
12.
J Med Chem ; 61(24): 11327-11340, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30457865

RESUMO

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Compostos de Espiro/síntese química , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Administração Intravenosa , Administração Oral , Animais , Antituberculosos/efeitos adversos , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1/antagonistas & inibidores , Feminino , Coração/efeitos dos fármacos , Humanos , Dose Máxima Tolerável , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Coelhos
13.
J Med Chem ; 61(8): 3595-3608, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29558124

RESUMO

We recently reported the discovery of nontoxic cyclam-derived compounds that are active against drug-resistant Mycobacterium tuberculosis. In this paper we report exploration of the structure-activity relationship for this class of compounds, identifying several simpler compounds with comparable activity. The most promising compound identified, possessing significantly improved water solubility, displayed high levels of bacterial clearance in an in vivo zebrafish embryo model, suggesting this compound series has promise for in vivo treatment of tuberculosis.


Assuntos
Antituberculosos/farmacologia , Compostos Aza/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Compostos Macrocíclicos/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Compostos Aza/síntese química , Compostos Aza/química , Carga Bacteriana/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Farmacorresistência Bacteriana , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Metais Pesados/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium marinum/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Peixe-Zebra
14.
Chemistry ; 24(7): 1573-1585, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29052259

RESUMO

Molecular switches have many potential applications in nanoscience and biomedicine. Transition metal complexes that can be switched from an inert, unreactive state to a catalytically active one by a simple change in conditions (e.g. pH shift) or by binding to a specific biomolecular target-so-called target-activated metal complexes (TAMCs)-hold particular allure as a means of harnessing the potent but at times indiscriminate reactivity of metal-based drugs. Towards this goal, we have prepared a series of ten structurally related ligands, each of which bears a different pendant side-arm functional group appended to a common macrocyclic core, along with copper(II) and nickel(II) complexes of these cyclam-based "molecular scorpionands". X-ray crystal structures reveal a variety of binding modes between pendant side-arm and metal centre that depend on the constituent donor atoms. To investigate the switchability of side-arm coordination in solution, spectrophotometric pH titrations were carried out for all 20 metal complexes. The majority of the complexes undergo spectroscopic changes that are consistent with a switch in pendant coordination state at a specific pH. This ligand series represents a comprehensive model platform from which to build pH-switchable metal complexes for applications in nanoscience and biomedicine.

15.
Chemistry ; 23(52): 12815-12824, 2017 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-28703303

RESUMO

Isopenicillin N synthase (IPNS) catalyses the four-electron oxidation of a tripeptide, l-δ-(α-aminoadipoyl)-l-cysteinyl-d-valine (ACV), to give isopenicillin N (IPN), the first-formed ß-lactam in penicillin and cephalosporin biosynthesis. IPNS catalysis is dependent upon an iron(II) cofactor and oxygen as a co-substrate. In the absence of substrate, the carbonyl oxygen of the side-chain amide of the penultimate residue, Gln330, co-ordinates to the active-site metal iron. Substrate binding ablates the interaction between Gln330 and the metal, triggering rearrangement of seven C-terminal residues, which move to take up a conformation that extends the final α-helix and encloses ACV in the active site. Mutagenesis studies are reported, which probe the role of the C-terminal and other aspects of the substrate binding pocket in IPNS. The hydrophobic nature of amino acid side-chains around the ACV binding pocket is important in catalysis. Deletion of seven C-terminal residues exposes the active site and leads to formation of a new type of thiol oxidation product. The isolated product is shown by LC-MS and NMR analyses to be the ene-thiol tautomer of a dithioester, made up from two molecules of ACV linked between the thiol sulfur of one tripeptide and the oxidised cysteinyl ß-carbon of the other. A mechanism for its formation is proposed, supported by an X-ray crystal structure, which shows the substrate ACV bound at the active site, its cysteinyl ß-carbon exposed to attack by a second molecule of substrate, adjacent. Formation of this product constitutes a new mode of reaction for IPNS and non-heme iron oxidases in general.


Assuntos
Aldeídos/metabolismo , Ésteres/metabolismo , Oxirredutases/metabolismo , Compostos de Sulfidrila/química , Aldeídos/química , Sítios de Ligação , Biocatálise , Domínio Catalítico , Cefalosporinas/biossíntese , Cefalosporinas/química , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Ésteres/química , Ferro/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Mutagênese , Oxirredução , Oxirredutases/genética , Oxigênio/química , Oxigênio/metabolismo , Penicilinas/biossíntese , Penicilinas/química , Especificidade por Substrato
16.
Analyst ; 142(11): 1953-1961, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28474014

RESUMO

A smartphone fluorimeter capable of time-based fluorescence intensity measurements at various temperatures is reported. Excitation is provided by an integrated UV LED (λex = 370 nm) and detection obtained using the in-built CMOS camera. A Peltier is integrated to allow measurements of the intensity over T = 10 to 40 °C. All components are controlled using a smartphone battery powered Arduino microcontroller and a customised Android application that allows sequential fluorescence imaging and quantification every δt = 4 seconds. The temperature dependence of fluorescence intensity for four emitters (rhodamine B, rhodamine 6G, 5,10,15,20-tetraphenylporphyrin and 6-(1,4,8,11-tetraazacyclotetradecane)2-ethyl-naphthalimide) are characterised. The normalised fluorescence intensity over time of the latter chemosensor dye complex in the presence of Zn2+ is observed to accelerate with an increasing rate constant, k = 1.94 min-1 at T = 15 °C and k = 3.64 min-1 at T = 30 °C, approaching a factor of ∼2 with only a change in temperature of ΔT = 15 °C. Thermally tuning these twist and bend associated rates to optimise sensor approaches and device applications is proposed.

17.
Molecules ; 22(2)2017 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-28125069

RESUMO

Small-molecule fluorescent probes play a myriad of important roles in chemical sensing. Many such systems incorporating a receptor component designed to recognise and bind a specific analyte, and a reporter or transducer component which signals the binding event with a change in fluorescence output have been developed. Fluorescent probes use a variety of mechanisms to transmit the binding event to the reporter unit, including photoinduced electron transfer (PET), charge transfer (CT), Förster resonance energy transfer (FRET), excimer formation, and aggregation induced emission (AIE) or aggregation caused quenching (ACQ). These systems respond to a wide array of potential analytes including protons, metal cations, anions, carbohydrates, and other biomolecules. This review surveys important new fluorescence-based probes for these and other analytes that have been reported over the past five years, focusing on the most widely exploited macrocyclic recognition components, those based on cyclam, calixarenes, cyclodextrins and crown ethers; other macrocyclic and non-macrocyclic receptors are also discussed.


Assuntos
Técnicas Biossensoriais , Corantes Fluorescentes/química , Íons/química , Compostos Macrocíclicos/química , Éteres de Coroa/química , Ciclodextrinas/química , Compostos Heterocíclicos/química , Pontos Quânticos
18.
Chembiochem ; 18(4): 338-351, 2017 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-27992105

RESUMO

ß-Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to ß-lactams: the prolonged, widespread (and at times reckless) use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with ß-lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all-carbon ring, the amide N is substituted by a tertiary C-H α to a ketone. Cyclobutanone analogues of various ß-lactam antibiotics have been investigated over the last 35 years, initially as prospective antibiotics in their own right and inhibitors of the ß-lactamase enzymes that impart resistance to ß-lactams. More recently they have been tested as inhibitors of other serine proteases and as mechanistic probes of ß-lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors with moderate activity against all classes of ß-lactamase; other compounds from this family inhibit Streptomyces R61 dd-carboxypeptidase/transpeptidase, human neutrophil elastase and porcine pancreatic elastase. But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising diversely functionalised cyclobutanone derivatives mean that only a limited number have been made (with limited structural diversity) and evaluated. This review surveys the different synthetic approaches that have been taken to these compounds, the investigations made to evaluate their biological activity and prospects for future developments in this area.


Assuntos
Inibidores de beta-Lactamases/síntese química , beta-Lactamas/química , beta-Lactamas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Butanonas/síntese química , Butanonas/química , Butanonas/farmacologia , Ciclização , Humanos , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia
19.
ChemistryOpen ; 5(4): 375-85, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27547648

RESUMO

Fluorescent molecular probes for metal ions have a raft of potential applications in chemistry and biomedicine. We report the synthesis and photophysical characterisation of 1,8-disubstituted-cyclam/naphthalimide conjugates and their zinc complexes. An efficient synthesis of 1,8-bis-(2-azidoethyl)cyclam has been developed and used to prepare 1,8-disubstituted triazolyl-cyclam systems, in which the pendant group is connected to triazole C4. UV/Vis and fluorescence emission spectra, zinc binding experiments, fluorescence quantum yield and lifetime measurements and pH titrations of the resultant bis-naphthalimide ligand elucidate a complex pattern of photophysical behaviour. Important differences arise from the inclusion of two fluorophores in the one probe and from the variation of triazole substitution pattern (dye at C4 vs. N1). Introducing a second fluorophore greatly extends fluorescence lifetimes, whereas the altered substitution pattern at the cyclam amines exerts a major influence on fluorescence output and metal binding. Crystal structures of two key zinc complexes evidence variations in triazole coordination that mirror the solution-phase behaviour of these systems.

20.
J Med Chem ; 59(12): 5917-21, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27214150

RESUMO

Tuberculosis (TB) accounted for 1.5 million deaths in 2014, and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tuberculosis, are nontoxic to human cell lines, and are active against multidrug-resistant M. tuberculosis strains, indicating a distinct mode of action. These compounds warrant further appraisal as novel agents to control TB in humans.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Antituberculosos/síntese química , Antituberculosos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade
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