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1.
Molecules ; 26(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34299385

RESUMO

An efficient and simple protocol for the synthesis of a new class of diverse bis(indolyl)pyridines analogues of the marine alkaloid nortopsentin has been reported. A one-pot four-component condensation of 3-cyanocarbomethylindole, various aldehyde, 3-acetylindole, and ammonium acetate in glacial acetic acid led to the formation of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridine-5-carbonitriles. Additionally, 2,6-bis(1H-indol-3-yl)-4-(benzofuran) pyridine-5-carbonitriles were prepared via a one-pot four-component condensation of 3-cyanocarbomethylindole, various N-substituted-indole-3-aldehydes, 2-acetylbenzofuran, and ammonium acetate. The synthesized compounds were evaluated for their ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 6538 and the Gram-negative strain Escherichia coli ATCC 25922. Some of the new compounds showed a marked selectivity against the Gram-positive and Gram-negative strains. Remarkably, five compounds 4b, 7a, 7c, 7d and 8e demonstrated good antibiofilm formation against S. aureus and E. coli. On the other hand, the release of reducing sugars and proteins from the treated bacterial strains over the untreated strains was considered to explain the disruption effect of the selected compound on the contact cells of S. aureus and E. coli. Out of all studied compounds, the binding energies and binding mode of bis-indole derivatives 7c and 7d were theoretically the best thymidylate kinase, DNA gyrase B and DNA topoisomerase IV subunit B inhibitors.


Assuntos
Alcaloides/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Inibidores Enzimáticos/farmacologia , Indóis/química , Biofilmes/efeitos dos fármacos , DNA Girase/química , DNA Topoisomerase IV/antagonistas & inibidores , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Piridinas/química
2.
J Med Chem ; 64(9): 6329-6357, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33929852

RESUMO

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.


Assuntos
Antibacterianos/farmacologia , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , Desenho de Fármacos , Fluoroquinolonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Camundongos , Inibidores da Topoisomerase II/química
3.
Eur J Med Chem ; 213: 113200, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33524686

RESUMO

The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase Ⅳ offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078-0.0625 µg/mL) and Gram-negative pathogens (MICs: range, 1-2 µg/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance.


Assuntos
Trifosfato de Adenosina/farmacologia , Antibacterianos/farmacologia , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Trifosfato de Adenosina/síntese química , Trifosfato de Adenosina/química , Antibacterianos/síntese química , Antibacterianos/química , Cristalografia por Raios X , DNA Topoisomerase IV/metabolismo , Relação Dose-Resposta a Droga , Escherichia coli/enzimologia , Escherichia coli/patogenicidade , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Staphylococcus aureus/enzimologia , Staphylococcus aureus/patogenicidade , Relação Estrutura-Atividade
4.
Sci Rep ; 11(1): 474, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436807

RESUMO

Topoisomerase IV (TopoIV) is a vital bacterial enzyme which disentangles newly replicated DNA and enables segregation of daughter chromosomes. In bacteria, DNA replication and segregation are concurrent processes. This means that TopoIV must continually remove inter-DNA linkages during replication. There exists a short time lag of about 10-20 min between replication and segregation in which the daughter chromosomes are intertwined. Exactly where TopoIV binds during the cell cycle has been the subject of much debate. We show here that TopoIV localizes to the origin proximal side of the fork trailing protein SeqA and follows the movement pattern of the replication machinery in the cell.


Assuntos
Cromossomos Bacterianos/metabolismo , Replicação do DNA/fisiologia , DNA Topoisomerase IV/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Proteínas de Escherichia coli/metabolismo , Inibidores da Topoisomerase II/farmacologia
5.
PLoS One ; 15(11): e0241780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33141832

RESUMO

The DNA topoisomerase complement of Streptococcus pneumoniae is constituted by two type II enzymes (topoisomerase IV and gyrase), and a single type I enzyme (topoisomerase I). These enzymes maintain the DNA topology, which is essential for replication and transcription. While fluoroquinolones target the type II enzymes, seconeolitsine, a new antimicrobial agent, targets topoisomerase I. We compared for the first time the in vitro effect of inhibition of topoisomerase I by seconeolitsine and of the type II topoisomerases by the fluoroquinolones levofloxacin and moxifloxacin. We used three isogenic non-encapsulated strains and five non-vaccine serotypes isolates belonging to two circulating pneumococcal clones, ST638 (2 strains) and ST1569V (3 strains). Each group contained strains with diverse susceptibility to fluoroquinolones. Minimal inhibitory concentrations, killing curves and postantibiotic effects were determined. Seconeolitsine demonstrated the fastest and highest bactericidal activity against planktonic bacteria and biofilms. When fluoroquinolone-susceptible planktonic bacteria were considered, seconeolitsine induced postantibiotic effects (1.00-1.87 h) similar than levofloxacin (1.00-2.22 h), but longer than moxifloxacin (0.39-1.71 h). The same effect was observed in sessile bacteria forming biofilms. Seconeolitsine induced postantibiotic effects (0.84-2.31 h) that were similar to those of levofloxacin (0.99-3.32 h) but longer than those of moxifloxacin (0.89-1.91 h). The greatest effect was observed in the viability and adherence of bacteria in the postantibiotic phase. Seconeolitsine greatly reduced the thickness of the biofilms formed in comparison with fluoroquinolones: 2.91 ± 0.43 µm (seconeolitsine), 7.18 ± 0.58 µm (levofloxacin), 17.08 ± 1.02 µm (moxifloxacin). When fluoroquinolone-resistant bacteria were considered, postantibiotic effects induced by levofloxacin and moxifloxacin, but not by seconeolitsine, were shorter, decreasing up to 5-fold (levofloxacin) or 2-fold (moxifloxacin) in planktonic cells, and up to 1.7 (levofloxacin) or 1.4-fold (moxifloxacin) during biofilm formation. Therefore, topoisomerase I inhibitors could be an alternative for the treatment of pneumococcal diseases, including those caused by fluoroquinolone-resistant isolates.


Assuntos
Antibacterianos/farmacologia , DNA Topoisomerase IV/antagonistas & inibidores , Fluoroquinolonas/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Inibidores da Topoisomerase I/farmacologia , Benzodioxóis/farmacologia , DNA Girase/metabolismo , Levofloxacino/farmacologia , Moxifloxacina/farmacologia , Fenantrenos/farmacologia , Streptococcus pneumoniae/enzimologia
6.
J Med Chem ; 63(14): 7773-7816, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32634310

RESUMO

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , Fluoroquinolonas/síntese química , Fluoroquinolonas/metabolismo , Fluoroquinolonas/toxicidade , Bactérias Gram-Negativas/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/toxicidade
7.
Molecules ; 25(12)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32549386

RESUMO

To develop new antimicrobial agents, a series of novel thiourea derivatives incorporated with different moieties 2-13 was designed and synthesized and their biological activities were evaluated. Compounds 7a, 7b and 8 exhibited excellent antimicrobial activity against all Gram-positive and Gram-negative bacteria, and the fungal Aspergillus flavus with minimum inhibitory concentration (MIC) values ranged from 0.95 ± 0.22 to 3.25 ± 1.00 µg/mL. Furthermore, cytotoxicity studies against MCF-7 cells revealed that compounds 7a and 7b were the most potent with IC50 values of 10.17 ± 0.65 and 11.59 ± 0.59 µM, respectively. On the other hand, the tested compounds were less toxic against normal kidney epithelial cell lines (Vero cells). The in vitro enzyme inhibition assay of 8 displayed excellent inhibitory activity against Escherichia coli DNA B gyrase and moderate one against E. coli Topoisomerase IV (IC50 = 0.33 ± 1.25 and 19.72 ± 1.00 µM, respectively) in comparison with novobiocin (IC50 values 0.28 ± 1.45 and 10.65 ± 1.02 µM, respectively). Finally, the molecular docking was done to position compound 8 into the E. coli DNA B and Topoisomerase IV active pockets to explore the probable binding conformation. In summary, compound 8 may serve as a potential dual E. coli DNA B and Topoisomerase IV inhibitor.


Assuntos
DNA Topoisomerase IV/antagonistas & inibidores , Tioureia/farmacologia , Inibidores da Topoisomerase II/química , Antibacterianos/farmacologia , DNA Girase/química , DNA Topoisomerase IV/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologia , Tioureia/análogos & derivados , Tioureia/química , Triazinas/química , Triazinas/farmacologia
8.
Molecules ; 25(10)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32422899

RESUMO

Antimicrobial resistance spurred by the overuse and misuse of antibiotics is a major global health concern, and of the Gram positive bacteria, S. aureus is a leading cause of mortality and morbidity. Alternative strategies to treat S. aureus infections, such as combination therapy, are urgently needed. In this study, a checkerboard method was used to evaluate synergistic interactions between nine thiosemicarbazides (4-benzoyl-1-(2,3-dichloro-benzoyl)thiosemicarbazides 1-5 and 4-aryl-1-(2-fluorobenzoyl)thiosemicarbazides 6-9) and conventional antibiotics against S. aureus ATCC 25923, which were determined as the fractional inhibitory concentration indices (FICIs). For these experiments, amoxicillin, gentamicin, levofloxacin, linezolid, and vancomycin were selected to represent the five antimicrobial classes most commonly used in clinical practice. With one exception of 7-vancomycin combination, none of the forty-five thiosemicarbazide-antibiotic combinations tested had an antagonistic effect, showing promising results with respect to a combination therapy. The synergic effect was observed for the 2-linezolid, 4-levofloxacin, 5-linezolid, 6-gentamicin, 6-linezolid, and 7-levofloxacin combinations. No interactions were seen in combination of the thiosemicarbazide with gentamicin or vancomycin, whereas all combinations with linezolid acted in additive or synergism, except for 6-gentamicin and 7-linezolid. The 4-(4-chlorophenyl)-1-(2-fluorobenzoyl)thiosemicarbazide 6 showed a clear preference for the potency; it affected synergistically in combinations with gentamicin or linezolid and additively in combinations with amoxicillin, levofloxacin, or vancomycin. In further studies, the inhibitory potency of the thiosemicarbazides against S. aureus DNA gyrase and topoisomerase IV was examined to clarify the molecular mechanism involved in their synergistic effect in combination with levofloxacin. The most potent synergist 6 at concentration of 100 µM was able to inhibit ~50% activity of S. aureus DNA gyrase, thereby suggesting that its anti-gyrase activity, although weak, may be a possible factor contributing to its synergism effect in combination with linezolid or gentamycin.


Assuntos
Amoxicilina/farmacologia , Antibacterianos/farmacologia , Gentamicinas/farmacologia , Levofloxacino/farmacologia , Linezolida/farmacologia , Semicarbazidas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacologia , Amoxicilina/química , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , DNA Girase/genética , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/genética , DNA Topoisomerase IV/metabolismo , Combinação de Medicamentos , Sinergismo Farmacológico , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Expressão Gênica , Gentamicinas/química , Humanos , Levofloxacino/química , Linezolida/química , Testes de Sensibilidade Microbiana , Semicarbazidas/química , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Vancomicina/química
9.
Bioorg Chem ; 97: 103672, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32145481

RESUMO

A novel, quick, environmentally safe, and one-pot synthesis of a series of N,N-bis(cyanoacetyl)hydrazine derivatives, bis-imino-2H-chromenes and bis-2-oxo-2H-chromene derivatives have been designed. Some selected newly synthesized compounds were investigated in vitro for their antibacterial activity. Compound 5j is the most toxic compound against Staphylococcus aureus with activity index 171%, followed by compound 15b with activity index 136% compared to standard drug ampicillin. Moreover, compound 15a is the most toxic compound against Escherichia coli with activity index 111% compared to standard drug gentamicin. Minimum inhibitory concentration (MIC) was carried out for compounds with high antibacterial activity. Compound 5j has good MIC (7.8 µg/ml) against Staphylococcus aureus while 15a has good MIC (31.25 µg/ml) against Streptococcus mutans which is better than MIC of the standard drug ampicillin (MIC = 62.5 µg/ml). Compounds 5j, 5k, 15a, 15b and 15e which have good MIC values were introduced to enzyme assay against DNA gyrase and topoisomerase IV. The results showed that compound 15a can strongly inhibit DNA gyrase and topoisomerase IV (IC50 = 27.30 and 25.52 µM respectively), compared to methotrexate as the standard drug (IC50 = 29.01 and 23.55 µM respectively). Structure-activity relationships were also discussed based on the biological and docking simulation results.


Assuntos
Antibacterianos/farmacologia , Bactérias/enzimologia , Cumarínicos/farmacologia , Hidrazinas/farmacologia , Inibidores da Topoisomerase/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Técnicas de Química Combinatória , Cumarínicos/síntese química , Cumarínicos/química , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Química Verde , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Simulação de Acoplamento Molecular , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Streptococcus mutans/efeitos dos fármacos , Streptococcus mutans/enzimologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
10.
J Med Chem ; 63(11): 5664-5674, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32027491

RESUMO

The emergence of bacterial resistance against life-saving medicines has forced the scientific community and pharmaceutical industry to take actions in the quest for novel antibacterials. These should not only overcome the existing bacterial resistance but also provide at least interim effective protection against emerging bacterial infections. Research into DNA gyrase and topoisomerase IV inhibitors has become a particular focus, with the description of a new class of bacterial topoisomerase type II inhibitors known as "novel bacterial topoisomerase inhibitors", NBTIs. Elucidation of the key structural modifications incorporated into these inhibitors and the impact these can have on their general physicochemical properties are detailed in this review. This defines novel bacterial topoisomerase inhibitors with promising antibacterial activities and potencies, which thus represent one potential example of the future "drugs for bad bugs", as identified by the World Health Organization.


Assuntos
Bactérias/enzimologia , DNA Topoisomerase IV/antagonistas & inibidores , Inibidores da Topoisomerase/química , Antibacterianos/química , Antibacterianos/metabolismo , Sítios de Ligação , Domínio Catalítico , DNA Girase/química , DNA Girase/metabolismo , DNA Topoisomerase IV/metabolismo , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase/metabolismo
11.
Bioorg Chem ; 94: 103437, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812260

RESUMO

Novel benzothiazole-based compounds were designed and synthesized as potential antimicrobial agents with dual DNA gyrase/topoisomerase IV inhibitory activity. The structures of the newly synthesized compounds were established on the basis of spectral (IR, NMR, MS) and elemental analyses. Most of the studied compounds possessed significant antimicrobial activity against tested bacteria and fungi. Compounds 4b and 7a were much more potent than reference standard ciprofloxacin against methicillin-resistant Staphylococcus aureus (MRSA) and a multi-drug resistant clinical isolate of Enterococcus faecium. Moreover, 7a was equipotent to nystatin against clinical isolate of Candida albicans. Both 4b and 7a inhibited DNA gyrase and topoisomerase IV at low micromolar levels and also displayed safety profiles much better than that of novobiocin in cytotoxicity assay.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Candida albicans/efeitos dos fármacos , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Relação Dose-Resposta a Droga , Enterococcus faecium/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
12.
Biochemistry ; 58(44): 4447-4455, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31617352

RESUMO

Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV but interact differently with the enzymes. This has led to the development of the "novel bacterial topoisomerase inhibitor" (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a naphthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases, including gyrase from Mycobacterium tuberculosis and gyrase and topoisomerase IV from Bacillus anthracis and Escherichia coli. GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. Therefore, we propose that the mechanistic basis for the antibacterial properties of NBTIs is bimodal in nature.


Assuntos
Antibacterianos/química , Clivagem do DNA/efeitos dos fármacos , Indóis/química , Naftiridinas/química , Piperidinas/química , Piridonas/química , Inibidores da Topoisomerase II/química , Bacillus anthracis/enzimologia , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , DNA Girase/química , DNA Topoisomerase IV/antagonistas & inibidores , DNA Bacteriano/efeitos dos fármacos , DNA de Cadeia Simples/efeitos dos fármacos , Escherichia coli/enzimologia , Mycobacterium tuberculosis/enzimologia
13.
Med Hypotheses ; 131: 109305, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443754

RESUMO

Infections due to resistant bacteria are the life-threatening and leading cause of mortality worldwide. The current therapy for bacterial infections includes treatment with various drugs and antibiotics. The misuse and over usage of these antibiotics leads to bacterial resistance. There are several mechanisms by which bacteria exhibit resistance to some antibiotics. These include drug inactivation or modification, elimination of antibiotics through efflux pumps, drug target alteration, and modification of metabolic pathway. However, it is difficult to treat infections caused by resistant bacteria by conventional existing therapy. In the present study binding affinities of some glitazones against ParE and MurE bacterial enzymes are investigated by in silico methods. As evident by extra-precision docking and binding free energy calculation (MM-GBSA) results, rivoglitazone exhibited higher binding affinity against both ParE and MurE enzymes compared to all other selected compounds. Further molecular dynamic (MD) simulations were performed to validate the stability of rivoglitazone/4MOT and rivoglitazone/4C13 complexes and to get insight into the binding mode of inhibitor. Thus, we hypothesize that structural modifications of the rivoglitazone scaffold can be useful for the development of an effective antibacterial agent.


Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , DNA Topoisomerase IV/antagonistas & inibidores , Peptídeo Sintases/antagonistas & inibidores , Tiazolidinedionas/farmacologia , Tiazolidinas/farmacologia , Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , DNA Topoisomerase IV/química , Resistência Microbiana a Medicamentos , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeo Sintases/química , Relação Estrutura-Atividade , Tiazolidinedionas/química , Tiazolidinas/química
14.
Eur J Med Chem ; 179: 576-590, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279292

RESUMO

A series of novel fluoroquinolone-Safirinium dye hybrids was synthesized by means of tandem Mannich-electrophilic amination reactions from profluorophoric isoxazolones and antibiotics bearing a secondary amino group at position 7 of the quinoline ring. The obtained fluorescent spiro fused conjugates incorporating quaternary nitrogen atoms were characterized by 1H NMR, IR, MS, and elemental analysis. All the synthetic analogues (3a-h and 4a-h) were evaluated for their in vitro antimicrobial, bactericidal, and antibiofilm activities against a panel of Gram positive and Gram-negative pathogenic bacteria. The most active Safirinium Q derivatives of lomefloxacin (4d) and ciprofloxacin (4e) exhibited molar-based antibacterial activities comparable to the unmodified drugs and displayed considerable inhibitory potencies in E. coli DNA gyrase supercoiling assays with IC50 values in the low micromolar range. Zwiterionic hybrids were noticeably less lipophilic than the parent quinolones in micellar electrokinetic chromatography (MECK) experiments. The tests performed in the presence of phenylalanine-arginine ß-naphthylamide (PAßN) or carbonyl cyanide m-chlorophenylhydrazone (CCCP) revealed that the conjugates are to some extent subject to bacterial efflux and cellular accumulation, respectively. Moreover, the hybrids did not exhibit notable cytotoxicity towards the HEK 293 control cell line and demonstrated low propensity for resistance development, as exemplified for compounds 3g and 4b. Finally, molecular docking experiments revealed that the synthesized compounds were able to bind in the fluoroquinolone-binding mode at S. aureus DNA gyrase and S. pneumoniae topoisomerase IV active sites.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Quinolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/metabolismo , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Quinolonas/química , Relação Estrutura-Atividade
15.
J Med Chem ; 62(16): 7445-7472, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31276392

RESUMO

Bacterial resistance is increasing rapidly, requiring urgent identification of new antibacterial drugs that are effective against multidrug-resistant pathogens. Novel bacterial topoisomerase inhibitors (NBTIs) provide a new strategy for investigating the well-validated DNA gyrase and topoisomerase IV targets while preventing cross-resistance issues. On this basis, starting from a virtual screening campaign and subsequent structure-based hit optimization guided by X-ray studies, a novel class of piperazine-like NBTIs with outstanding enzymatic activity against Staphylococcus aureus and Escherichia coli DNA gyrase and topoisomerase IV was identified. Notably, compounds (±)-33, (±)-35, and (±)-36 with potent and balanced multitarget enzymatic profiles exhibited excellent efficacy against selected Gram-positive and Gram-negative pathogens, as well as clinically relevant resistant strains. Overall, the new NBTI chemotype described herein, owing to the broad-spectrum antibacterial activity and favorable in vitro safety profile, might serve as a basis for the development of novel treatments against serious infections.


Assuntos
DNA Topoisomerase IV/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase/farmacologia , Sequência de Aminoácidos , Infecções Bacterianas/microbiologia , Infecções Bacterianas/prevenção & controle , DNA Girase/genética , DNA Girase/metabolismo , DNA Topoisomerase IV/genética , DNA Topoisomerase IV/metabolismo , Escherichia coli/enzimologia , Escherichia coli/genética , Testes de Sensibilidade Microbiana , Modelos Químicos , Estrutura Molecular , Homologia de Sequência de Aminoácidos , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genética , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
16.
Eur J Med Chem ; 179: 166-181, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254919

RESUMO

This work did a new exploration towards aminothiazolquinolone oximes as potentially multi-targeting antimicrobial agents. A class of novel hybrids of quinolone, aminothiazole, piperazine and oxime fragments were designed for the first time, conveniently synthesized as well as characterized by 1H NMR, 13C NMR and HRMS spectra. Biological activity showed that some of the synthesized compounds exhibited good antimicrobial activities in comparison with the reference drugs. Especially, O-methyl oxime derivative 10b displayed excellent inhibitory efficacy against MRSA and S. aureus 25923 with MIC values of 0.009 and 0.017 mM, respectively. Further studies indicated that the highly active compound 10b showed low toxicity toward BEAS-2B and A549 cell lines and no obvious propensity to trigger the development of bacterial resistance. Quantum chemical studies have also been conducted and rationally explained the structural features essential for activity. The preliminarily mechanism exploration revealed that compound 10b could not only exert efficient membrane permeability by interfering with the integrity of cells, bind with topoisomerase IV-DNA complex through hydrogen bonds and π-π stacking, but also form a steady biosupramolecular complex by intercalating into DNA to exert the efficient antibacterial activity. The supramolecular interaction between compound 10b and human serum albumin (HSA) was a static quenching, and the binding process was spontaneous, where hydrogen bonds and van der Waals force played vital roles in the supramolecular transportation of the active compound 10b by HSA.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Oximas/farmacologia , Quinolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , DNA/efeitos dos fármacos , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Relação Dose-Resposta a Droga , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oximas/síntese química , Oximas/química , Teoria Quântica , Quinolonas/síntese química , Quinolonas/química , Albumina Sérica Humana/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
17.
ACS Infect Dis ; 5(7): 1115-1128, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31041863

RESUMO

The development of new therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) is needed to counteract the significant threat that MRSA presents to human health. Novel inhibitors of DNA gyrase and topoisomerase IV (TopoIV) constitute one highly promising approach, but continued optimization is required to realize the full potential of this class of antibiotics. Herein, we report further studies on a series of dioxane-linked derivatives, demonstrating improved antistaphylococcal activity and reduced hERG inhibition. A subseries of analogues also possesses enhanced inhibition of the secondary target, TopoIV.


Assuntos
Antibacterianos/síntese química , DNA Girase/metabolismo , Dioxanos/química , Staphylococcus aureus Resistente à Meticilina/enzimologia , Inibidores da Topoisomerase/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , DNA Girase/química , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , DNA Topoisomerase IV/metabolismo , Regulação para Baixo , Canal de Potássio ERG1/metabolismo , Humanos , Células K562 , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologia
18.
Molecules ; 24(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862066

RESUMO

Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25⁻0.5 µg/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·kg-1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 µg/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Berberina/química , Berberina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Berberina/análogos & derivados , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 167: 269-290, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776691

RESUMO

ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 µM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 µM, 1.56 µM, 0.78 µM and 0.72 µM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 µM on both strains, and MIC value of 32 µM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.


Assuntos
Antibacterianos/química , DNA Topoisomerase IV/antagonistas & inibidores , Pirrolidinas/química , Inibidores da Topoisomerase II/farmacologia , Amidas/química , Antibacterianos/farmacologia , DNA Girase/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Inibidores da Topoisomerase II/química
20.
Bioorg Chem ; 85: 308-318, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30654222

RESUMO

A series of new 1,2,4-triazole and 1,3,4-oxadiazole derivatives was obtained via several steps sequential reactions of phenyl piperazine. Then, these compounds were converted to the corresponding fluoroquinolone hybrids via one pot three component Mannich reaction. All the reactions were examined under conventional and microwave mediated conditions, and optimum conditions were determined. The effect of different solvents and microwave power on microwave prompted reactions was investigated as well. All the newly synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR and EI MS spectral techniques. The antimicrobial activity, DNA gyrase and Topoisomerase IV inhibition potentials were performed. The results obtained showed that fluoroquinolone hybrids possess good antimicrobial activity. Moreover, Fluoroquinolone-azole-piperazine hybrids synthesized in the present study displayed excellent DNA gyrase inhibition. To unveil the interaction mode of compounds to receptor, a molecular docking study was performed. With an average least binding energy of -9.5 kcal/mol, all compounds were found to have remarkable inhibitory potentials against DNA gyrase (E. coli).


Assuntos
Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Piperazinas/farmacologia , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/metabolismo , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Enterococcus faecalis/efeitos dos fármacos , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/metabolismo , Fluoroquinolonas/síntese química , Fluoroquinolonas/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Testes de Sensibilidade Microbiana , Micro-Ondas , Simulação de Acoplamento Molecular , Piperazinas/síntese química , Piperazinas/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/farmacologia , Triazóis/síntese química , Triazóis/metabolismo
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