Novel hybrids of metronidazole and quinolones: Synthesis, bioactive evaluation, cytotoxicity, preliminary antimicrobial mechanism and effect of metal ions on their transportation by human serum albumin
“…Synthesis of monosubstituted o-phenylenediamines (7,9,11) and chloromethyl benzimidazoles (8, 10,12):I ntermediates 7-12 were prepared according to procedures reported in the literature, starting from o-phenylenediamine. [12,42] Synthesis of 4a:Am ixture of 3 (500 mg, 1.854 mmol), potassium carbonate (256 mg, 1.854 mmol), and sodium iodide (278 mg, 1.854 mmol) in acetonitrile (10 mL) was stirred at 70 8Cf or 0.5 h. After the mixture was cooled to room temperature, compound 8a (361 mg, 1.854 mmol) was added.…”
Section: Methodsmentioning
confidence: 99%
“…[1][2][3] In particular,t he synthesis of the fluoroquinolone family of compounds has made ag reat contribution to anti-infective agents, such as norfloxacin,c iprofloxacin, levofloxacin, and moxifloxacin. [6][7][8] However, the overuse of quinolones to manage bacterial infections has led to the evolution and widespread distribution of resistant strains,s uch as Streptococcus pneumoniae, Escherichia coli,a nd Staphylococcus aureus. [6][7][8] However, the overuse of quinolones to manage bacterial infections has led to the evolution and widespread distribution of resistant strains,s uch as Streptococcus pneumoniae, Escherichia coli,a nd Staphylococcus aureus.…”
Section: Introductionmentioning
confidence: 99%
“…[4,5] The antimicrobialm echanism revealed that this type of drug could target DNA gyrase or topoisomerase IV by binding with enzyme-DNAb inaryc omplexes to form ternary supramolecular complexes, therebyo bstructing DNA replication and finally resulting in bacterial death. [6][7][8] However, the overuse of quinolones to manage bacterial infections has led to the evolution and widespread distribution of resistant strains,s uch as Streptococcus pneumoniae, Escherichia coli,a nd Staphylococcus aureus. [9][10][11] It was reported that resistance to quinolones was mainly attributed to mutations of somek ey enzymesi nq uinolone-resistant pathogens.…”
A series of benzimidazole-quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2-fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV-DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.
“…Synthesis of monosubstituted o-phenylenediamines (7,9,11) and chloromethyl benzimidazoles (8, 10,12):I ntermediates 7-12 were prepared according to procedures reported in the literature, starting from o-phenylenediamine. [12,42] Synthesis of 4a:Am ixture of 3 (500 mg, 1.854 mmol), potassium carbonate (256 mg, 1.854 mmol), and sodium iodide (278 mg, 1.854 mmol) in acetonitrile (10 mL) was stirred at 70 8Cf or 0.5 h. After the mixture was cooled to room temperature, compound 8a (361 mg, 1.854 mmol) was added.…”
Section: Methodsmentioning
confidence: 99%
“…[1][2][3] In particular,t he synthesis of the fluoroquinolone family of compounds has made ag reat contribution to anti-infective agents, such as norfloxacin,c iprofloxacin, levofloxacin, and moxifloxacin. [6][7][8] However, the overuse of quinolones to manage bacterial infections has led to the evolution and widespread distribution of resistant strains,s uch as Streptococcus pneumoniae, Escherichia coli,a nd Staphylococcus aureus. [6][7][8] However, the overuse of quinolones to manage bacterial infections has led to the evolution and widespread distribution of resistant strains,s uch as Streptococcus pneumoniae, Escherichia coli,a nd Staphylococcus aureus.…”
Section: Introductionmentioning
confidence: 99%
“…[4,5] The antimicrobialm echanism revealed that this type of drug could target DNA gyrase or topoisomerase IV by binding with enzyme-DNAb inaryc omplexes to form ternary supramolecular complexes, therebyo bstructing DNA replication and finally resulting in bacterial death. [6][7][8] However, the overuse of quinolones to manage bacterial infections has led to the evolution and widespread distribution of resistant strains,s uch as Streptococcus pneumoniae, Escherichia coli,a nd Staphylococcus aureus. [9][10][11] It was reported that resistance to quinolones was mainly attributed to mutations of somek ey enzymesi nq uinolone-resistant pathogens.…”
A series of benzimidazole-quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2-fluorobenzyl derivative 5 b (ethyl 7-chloro-6-fluoro-1-[[1-[(2-fluorophenyl)methyl]benzimidazol-2-yl]methyl]-4-oxo-quinoline-3-carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep-2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV-DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug-resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.
“…PMQR-positive isolates present a low-level of resistance to quinolones (only a small reduction in susceptibility to nalidixic acid). However, the ability to highlight pre-existing resistance mechanisms, such as chromosomal mutations in target regions of quinolones that still allow the selection of resistant mutants to quinolone concentrations (therapeutic doses), emphasize the importance of studying these genes (Cui et al, 2014). …”
Salmonella spp. is an important zoonotic pathogen related to foodborne diseases. Despite that quinolones/fluoroquinolones are considered a relevant therapeutic strategy against resistant isolates, the increase in antimicrobial resistance is an additional difficulty in controlling bacterial infections caused by Salmonella spp. Thus, the acquisition of resistance to quinolones in Salmonella spp. is worrisome to the scientific community along with the possibility of transmission of resistance through plasmids. This study investigated the prevalence of plasmid-mediated quinolone resistance (PMQR) in Salmonella spp. and its association with fluoroquinolone susceptibility in Brazil. We evaluated 129 isolates, 39 originated from food of animal sources, and 14 from environmental samples and including 9 from animals and 67 from humans, which were referred to the National Reference Laboratory of Enteric Diseases (NRLEB/IOC/RJ) between 2009 and 2013. These samples showed a profile of resistance for the tested quinolones/fluoroquinolones. A total of 33 serotypes were identified; S. Typhimurium (63) was the most prevalent followed by S. Enteritidis (25). The disk diffusion test showed 48.8% resistance to enrofloxacin, 42.6% to ciprofloxacin, 39.53% to ofloxacin, and 30.2% to levofloxacin. According to the broth microdilution test, the resistance percentages were: 96.1% to nalidixic acid, 64.3% to enrofloxacin, 56.6% to ciprofloxacin, 34.1% to ofloxacin, and 30.2% to levofloxacin. Qnr genes were found in 15 isolates (8 qnrS, 6 qnrB, and 1 qnrD), and the aac(6′)-Ib gene in 23. The integron gene was detected in 67 isolates with the variable region between ±600 and 1000 bp. The increased detection of PMQR in Salmonella spp. is a serious problem in Public Health and must constantly be monitored. Pulsed-field gel electrophoresis was performed to evaluated clonal profile among the most prevalent serovars resistant to different classes of quinolones. A total of 33 pulsotypes of S. Typhimurium were identified with a low percentage of genetic similarity (≤65%). This result demonstrates the presence of high diversity in the resistant clones evaluated in this study.
“…Compound 70d was tested in binding assay with calf-thymus DNA and exhibited stronger interferation with nucleic acid than norfloxacin. These conjugates exhibited also good aqueous solubility, which combined make them good potential drug candidates [152].
…”
This review is aimed to provide extensive survey of quinolones and fluoroquinolones for a variety of applications ranging from metal complexes and nanoparticle development to hybrid conjugates with therapeutic uses. The review covers the literature from the past 10 years with emphasis placed on new applications and mechanisms of pharmacological action of quinolone derivatives. The following are considered: metal complexes, nanoparticles and nanodrugs, polymers, proteins and peptides, NO donors and analogs, anionic compounds, siderophores, phosphonates, and prodrugs with enhanced lipophilicity, phototherapeutics, fluorescent compounds, triazoles, hybrid drugs, bis-quinolones, and other modifications. This review provides a comprehensive resource, summarizing a broad range of important quinolone applications with great utility as a resource concerning both chemical modifications and also novel hybrid bifunctional therapeutic agents.Graphical abstract
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