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The structure-activity relationships (SAR) of quinolones. The antibacterial activity of quinolones is improved by modifications of different substituents in different positions. The color of the groups in the bracket correlates with the type of activities.
Source publication
The quinolone antibiotics arose in the early 1960s, with the first examples possessing a narrow-spectrum activity with unfavorable pharmacokinetic properties. Over time, the development of new quinolone antibiotics has led to improved analogs with an expanded spectrum and high efficacy. Nowadays, quinolones are widely used for treating a variety of...
Context in source publication
Citations
... Then FDA (Food and Drug Administration) approved this compound for the urinary tract infections and against Gram-negative bacteria. 8 By adding fluorine, the fluoroquinolone family appeared, then FDA documented more than twenty compounds of this family Kassaret al.: Synthesis, Characterization and Biological Activity Evaluation of ... circulating in the market with antimicrobial effects 1000 times stronger than nalidixic acid. 9 Fluorine's key features, at the position 6 ( Figure 1), can influence pharmacological, pharmacodynamic and pharmacokinetic effects, as well as biological activity. ...
Quinoline and its derivatives are a family with unique medicinal properties, including antibacterial effects. It was assumed that the four quinoline derivatives 1, 2, 3 and 4 had significant activity against pathogenic bacteria. These compounds were synthesized and characterized by TLC, IR, 1H NMR, and 13C NMR analyses. The biological activity of compounds was determined as inhibition zone (IZ) in mm. For compound 1 IZ was 19 ± 0.22 against Klebsiella pneumoniae, IZ was 18 ± 0.22 against Bacillus subtilis, and IZ was 17 ± 0.22 against Staphylococcus aureus. 2 displayed IZ of 18 ± 0.22 against both Klebsiella pneumoniae and Bacillus subtilis. 3 showed IZ of 17 ± 0.22 against Staphylococcus aureus. 4 displayed IZ of 21 ± 0.22, thus showing a higher inhibitory activity against Escherichia coli, than ciprofloxacin. These results demonstrate the potential of the synthesized compounds to work as antibacterial drugs against these strains by inhibiting or deactivating the target proteins.
... Tissue ischaemia causes hypoxia and necrosis, which can eventually lead to chronic infections. Ciprofloxacin (CIP) is a quinolone antibiotic that causes bacterial death due to the inhibition of DNA synthesis as a result of topoisomerase II disruption (Pham et al. 2019). Koźmiński et al. (2021) radiolabelled ciprofloxacin with 99m Tc directly and with 89 Ga via DOTA-NHS as chelator (see Fig. 23). ...
Background
Infection remains a major cause of morbidity and mortality, regardless of advances in antimicrobial therapy and improved knowledge of microorganisms. With the major global threat posed by antimicrobial resistance, fast and accurate diagnosis of infections, and the reliable identification of intractable infection, are becoming more crucial for effective treatment and the application of antibiotic stewardship. Molecular imaging with the use of nuclear medicine allows early detection and localisation of infection and inflammatory processes, as well as accurate monitoring of treatment response. There has been a continuous search for more specific radiopharmaceuticals to be utilised for infection imaging. This review summarises the most prominent discoveries in specifically bacterial infection imaging agents over the last five years, since 2019.
Main body
Some promising new radiopharmaceuticals evaluated in patient studies are reported here, including radiolabelled bacterial siderophores like [⁶⁸Ga]Ga-DFO-B, radiolabelled antimicrobial peptide/peptide fragments like [⁶⁸Ga]Ga-NOTA-UBI29-41, and agents that target bacterial synthesis pathways (folic acid and peptidoglycan) like [¹¹C]para-aminobenzoic acid and D-methyl-[¹¹C]-methionine, with clinical trials underway for [¹⁸F]fluorodeoxy-sorbitol, as well as for ¹¹C- and ¹⁸F-labelled trimethoprim.
Conclusion
It is evident that a great deal of effort has gone into the development of new radiopharmaceuticals for infection imaging over the last few years, with remarkable progress in preclinical investigations. However, translation to clinical trials, and eventually clinical Nuclear Medicine practice, is apparently slow. It is the authors’ opinion that a more structured and harmonised preclinical setting and well-designed clinical investigations are the key to reliably evaluate the true potential of the newly proposed infection imaging agents.
... However, modification of their chemical structure allowed for the development of FQs active against Gram-positive infections of the respiratory tract. Inhibition of the catalytic cycle of the enzymes DNA gyrase and topoisomerase IV, which are responsible for the replication and transcription of bacterial DNA, is the main mechanism responsible for the antibacterial action of fluoroquinolones [3,[6][7][8]. Recently, a similar effect of FQs was shown on the eukaryotic analog topoisomerase II. ...
Antibacterial fluoroquinolones have emerged as potential anticancer drugs, thus prompting the synthesis of novel molecules with improved cytotoxic characteristics. Ciprofloxacin and norfloxacin derivatives, previously synthesized by our group, showed higher anticancer potency than their progenitors. However, no information about their mechanisms of action was reported. In this study, we selected the most active among these promising molecules and evaluated, on a panel of breast (including those triple-negative) and bladder cancer cell lines, their ability to induce cell cycle alterations and apoptotic and necrotic cell death through cytofluorimetric studies. Furthermore, inhibitory effects on cellular migration, metalloproteinase, and/or acetylated histone protein levels were also evaluated by the scratch/wound healing assay and Western blot analyses, respectively. Finally, the DNA relaxation assay was performed to confirm topoisomerase inhibition. Our results indicate that the highest potency previously observed for the derivatives could be related to their ability to induce G2/M cell cycle arrest and apoptotic and/or necrotic cell death. Moreover, they inhibited cellular migration, probably by reducing metalloproteinase levels and histone deacetylases. Finally, topoisomerase inhibition, previously observed in silico, was confirmed. In conclusion, structural modifications of progenitor fluoroquinolones resulted in potent anticancer derivatives possessing multiple mechanisms of action, potentially exploitable for the treatment of aggressive/resistant cancers.
... It is well established that the chemical structure of FQs is closely related to their genotoxic potential. Firstly, the fluorine atom in C6 improves their antibacterial efficacy but, unfortunately, also increases the genotoxicity of the compounds [226,227]. Secondly, QSAR and 3D Pharmacophore in silico models showed that the C5 and C7 positions are the main determinants of FQ genotoxicity [228]. It is worthy of note that new FQ derivatives, based on this prediction model, present lower genotoxicity and higher efficacy [228]. ...
Fluoroquinolones (FQs) have achieved significant success in both human and veterinary medicine. However, regulatory authorities have recommended limiting their use, firstly because they can have disabling side effects; secondly, because of the need to limit the spread of antibiotic resistance. This review addresses another concerning consequence of the excessive use of FQs: the freshwater environments contamination and the impact on non-target organisms. Here, an overview of the highest concentrations found in Europe, Asia, and the USA is provided, the sensitivity of various taxa is presented through a comparison of the lowest EC50s from about a hundred acute toxicity tests, and primary mechanisms of FQ toxicity are described. A risk assessment is conducted based on the estimation of the Predicted No Effect Concentration (PNEC). This is calculated traditionally and, in a more contemporary manner, by constructing a normalized Species Sensitivity Distribution curve. The lowest individual HC5 (6.52 µg L−1) was obtained for levofloxacin, followed by ciprofloxacin (7.51 µg L−1), sarafloxacin and clinafloxacin (12.23 µg L−1), and ofloxacin (17.12 µg L−1). By comparing the calculated PNEC with detected concentrations, it is evident that the risk cannot be denied: the potential impact of FQs on freshwater ecosystems is a further reason to minimize their use.
... To deal with infections caused by drug-resistant bacteria, current clinical practice often involves the utilization of high-dose antibiotic therapy or a combination of multiple antibiotics (Courjon & Del Guidice, 2021;Michelangeli et al., 2018;Vincent et al., 2016). Antibiotics commonly employed in clinical practice can be categorized into the following seven groups based on their chemical structures: (1) β-lactam antibiotics (e.g., penicillins, cephalosporins) (Lima et al., 2020;Zabiszak et al., 2023); (2) Macrolide antibiotics (e.g., erythromycin, azithromycin) (Chen, Gao, et al., 2023;Chen, Leimer, et al., 2023;Chen, Qi, et al., 2023;Fostier et al., 2023); (3) Peptide antibiotics (e.g., vancomycin, polymyxin) Tian, Su, et al., 2023); (4) Aminoglycoside antibiotics (e.g., streptomycin, kanamycin) (Dove et al., 2022;Yang, Song, Dong, et al., 2023;Yang, Song, Yin, et al., 2023;Yang, Wang, Wang, et al., 2023); (5) Tetracycline antibiotics (e.g., tetracycline, doxycycline) (Grossman, 2016;LaPlante et al., 2022); (6) Quinolone antibiotics (e.g., ciprofloxacin, ofloxacin) (Pham et al., 2019); (7) Sulfonamide antibiotics (e.g., sulfadiazine) (Zhu, Pang, et al., 2022;. Furthermore, certain antimicrobial peptides and surface-active substances have also demonstrated the ability to eliminate bacteria or suppress genes associated with biofilm synthesis (Xuan et al., 2023). ...
The misuse of antibiotics has led to increased bacterial resistance, posing a global public health crisis and seriously endangering lives. Currently, antibiotic therapy remains the most common approach for treating bacterial infections, but its effectiveness against multidrug‐resistant bacteria is diminishing due to the slow development of new antibiotics and the increase of bacterial drug resistance. Consequently, developing new a\ntimicrobial strategies and improving antibiotic efficacy to combat bacterial infection has become an urgent priority. The emergence of nanotechnology has revolutionized the traditional antibiotic treatment, presenting new opportunities for refractory bacterial infection. Here we comprehensively review the research progress in nanotechnology‐based antimicrobial drug delivery and highlight diverse platforms designed to target different bacterial resistance mechanisms. We also outline the use of nanotechnology in combining antibiotic therapy with other therapeutic modalities to enhance the therapeutic effectiveness of drug‐resistant bacterial infections. These innovative therapeutic strategies have the potential to enhance bacterial susceptibility and overcome bacterial resistance. Finally, the challenges and prospects for the application of nanomaterial‐based antimicrobial strategies in combating bacterial resistance are discussed.
This article is categorized under: Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures
Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease
... Quinolone antibiotics, ofloxacin, ciprofloxacin, and norfloxacin, are a popular class of antibiotics that have been found to have wide applications in the treatment of various diseases in mammals. The antibiotics are used for respiratory (Dan et al. 2001), eye (Alhakamy et al. 2022;Pearce et al. 2022), and urinary tract (Naber et al. 2000;Reid et al. 2000) infection therapy, multidrug-resistant tuberculosis (Lourenço et al. 2007;Hwang et al. 2008), and leprosy (Yang et al. 2023a) due to their high and broad spectrum of antibacterial activity and availability (Dhiman et al. 2019;Pham et al. 2019). These weakly metabolized antibiotics can easily toxify both surface and groundwater, affecting the quality of aquatic organisms, and causing chronic diseases in humans and animals, due to the growth of antibacterial resistance (Deng et al. 2022;Yin et al. 2022). ...
The sphere-shaped zinc oxide (ZnO) photocatalyst was synthesized by the homogeneous precipitation method, using Zn(CH3COO)2·2H2O as a zinc precursor and NH4OH as a precipitating agent. The morphology and crystal structure of the prepared ZnO sample were studied by XRD, SEM, FT-IR, XPS, zeta potential measurements, and a low-temperature nitrogen adsorption-desorption technique. The optical characteristics of ZnO were determined by UV − Vis diffuse reflectance spectroscopy. ZnO photocatalyst performance of up to 100% within 210 min was observed in the photodegradation of the ofloxacin antibiotic under ultraviolet (UV) irradiation. The effect of antibiotic concentration, heavy metal ions, and water sources on the photocatalytic activity of ZnO demonstrated both the potential of its application under different conditions, and a good adaptability of this photocatalyst. The photodegradation reaction correlated well with the first-order kinetics model, with a rate constant of 0.0173 min⁻¹. The reusability of the photocatalyst was verified after three cycles of use. Admittedly, photogenerated electrons and holes played a key role in removal of the antibiotic. This work showed the suitability of prepared ZnO for antibiotic removal, and its potential use for environmental protection.
... Whereas, when the modifi cation was done on R 1 by the addition of a cyclopropyl group, the overall potency of the drug was enhanced. Apart from the latter, extensive studies were made on the improvement of the activity of fl uoroquinolones upon the structural modifi cations and all could be summarized in Figure 3. Figure 3 shows that a potent drug against Gram-positive and Gram-negative organisms could be designed as well as upon the aim, of different compounds could be synthesized [7]. ...
... DNA, during the stage of synthesis, opens up its double strands allowing the transcription with the complementary base pairing to occur. The enzymes responsible for such action in bacteria are known as topoisomerase-II, DNA gyrase, and DNA topoisomerase IV [7]. Once quinolones enter the scene, the inhibition could happen in two manners depending upon the concentration. ...
Fluoroquinolones (FQs) are widely used antibiotics for therapeutic purposes, yet their extensive usage and unwise disposal led to antibiotic resistance as well as their widespread across the environment and becoming a major contaminates in water bodies as the wastewater treatment plants are not capable removing of FQs completely. Knowing the latter, the researchers endeavored to find techniques for the detection and removal of such contaminates from the disposed water from different facilities. This review highlights some of the recently and currently developed techniques for detection and removal. It discusses also different adsorbents used to remove FQs from wastewater. All in all, the removal of such leading contaminates from water would inhibit their spread across different environmental spheres thus promoting better environmental health.
... [10] Nalidixic acid is the first member of the quinolones family; nonetheless, it is a restricted spectrum antibiotic that was exclusively used to treat urinary tract infections. [8] The second generation of this family included a fluorine atom at the sixth carbon atom to boost activity. One such example is ofloxacin, a broad range antibiotic that works against both gram positive and gram negative bacteria. ...
In the late nineteenth century, diseases were assumed to be linked to the presence of microbes. The mortality rate dropped after the antiseptic approach was used. Good cleanliness and sanitation helped to drastically cut the death rate from infectious diseases. Antimicrobials were produced, and numerous pathogenic diseases were eradicated. Essential antibacterial drugs that are frequently utilized in clinical therapies include fluoroquinolones. Their synthetic pathway, action and therapeutic uses are described in this review. Their primary mechanism of action is the inhibition of bacterial DNA gyrase and topoisomerase IV, which are essential enzymes involved in transcription and DNA replication. Fluorination is one of the important structural change that improves their efficacy and spectrum of activity against a variety of infections. To enhance pharmacokinetics, substituent modification, fluorination, and cyclization of heterocycles are used in synthesis. Advances in synthetic chemistry have produced compounds that exhibit increased activity and decreased resistance. Clinical applications include treating respiratory, urinary tract, cutaneous, and gastrointestinal diseases. These drugs also show activity like antitumor, wound healing, antimycobacterial, etc. This review aims to provide researchers and academicians a brief account about the bacterial action, synthesis and clinical applications in antimicrobial therapy.
... DNA gyrase and DNA topoisomerase IV are bacterial enzymes of the topoisomerase II class that carry out this unwinding process. Quinolones work by preventing these enzymes from functioning, which halts the production process [25]. The quinolones have two targets among these enzymes: DNA gyrase and the more recently identified DNA topoisomerase IV. ...
... Second-generation quinolones including enoxacin, norfloxacin, and ciprofloxacin were produced by fluorine atom modification. Third-generation quinolones like gemifloxacin, moxifloxacin, rovafloxacin, and garenoxacin were produced by replacing the piperazine ring [25]. Among all quinolone alterations, arthralgia and gastrointestinal side effects are said to be the most frequent ones. ...
Prevalence of microbial infections and new rising pathogens are signified as causative agent for variety of serious and lethal health crisis in past years. Despite medical advances, bacterial and fungal infections continue to be a rising problem in the health care system. As more bacteria develop resistance to antibiotics used in therapy, and as more invasive microbial species develop resistance to conventional antimicrobial drugs. Relevant published publications from the last two decades, up to 2024, were systematically retrieved from the MEDLINE/PubMed, SCOPUS, EMBASE, and WOS databases using keywords such as quinolones, anti-infective, antibacterial, antimicrobial resistance and patents on quinolone derivatives. With an approach of considerable interest towards novel heterocyclic derivatives as novel anti-infective agents, researchers have explored these as essential tools in vistas of drug design and development. Among heterocycles, quinolones have been regarded extremely essential for the development of novel derivatives, even able to tackle the associated resistance issues. The quinolone scaffold with its bicyclic structure and specific functional groups such as the carbonyl and acidic groups, is indeed considered a valuable functionalities for further lead generation and optimization in drug discovery. Besides, the substitution at N-1, C-3 and C-7 positions also subjected to be having a significant role in anti-infective potential. In this article, we intend to highlight recent quinolone derivatives based on the SAR approach and anti-infective potential such as antibacterial, antifungal, antimalarial, antitubercular, antitrypanosomal and antiviral activities. Moreover, some recent patents granted on quinolone-containing derivatives as anti-infective agents have also been highlighted in tabular form. Due consideration of this, future research in this scaffold is expected to be useful for aspiring scientists to get pharmacologically significant leads.
Graphical abstract
Several Quinolone derivatives based on the SAR approach as potent antimicrobial agents which combat antimicrobial resistance.
... Most of the LAB isolates of this research were resistant to ofloxacin and ciprofloxacin (both synthetic quinolone antibiotics of second generation), and penicillin (β-lactam antibiotic). Although first and second-generation quinolones are usually more effective against some Gram-positive bacteria than third and fourth-generation quinolones, these drugs are used mostly for Gram-negative bacteria (Pham et al., 2019). Unfortunately, there is an increasing resistance to penicillin by Gram-positive bacteria, even pathogenic bacteria, because of horizontal spreading of penicillinase plasmids or by horizontal gene transfer that synthesizes penicillin-binding protein (Jubeh et al., 2020). ...
