Fluoroquinolone Derivatives Research Articles

Exploration of Specific Fluoroquinolone Interaction with SARS-CoV-2 Main Protease (Mpro) to Battle COVID-19: DFT, Molecular Docking, ADME and Cardiotoxicity Studies.

Herein, the pharmacokinetic profiles, binding interactions, and molecular properties of fluoroquinolone derivatives as prospective antiviral drugs are examined using a combination of docking, ADME, and DFT simulations. The effectiveness of the ligands is compared with the clinically tested and FDA-authorized medicine remdesivir. The findings demonstrated encouraging binding energies, indicating possible inhibitory effectiveness against SARS-CoV-2 Mpro. The fluoroquinolone derivatives also exhibit promising ADME characteristics, although compounds 5, 6, 9, 12-20 possess poor values, suggesting that oral administration may be possible. The potential of the selected compounds as SARS-CoV-2 Mpro inhibitors is thoroughly understood because of the integrated analysis of DFT, with compound 11 demonstrating the highest energy gap of 0.2604 eV of, docking with viral targets with docking scores of -7.9 to -5.9 kcal/mol, with compound 18 demonstrating the highest docking score, which is at the 13th position in energy difference in the DFT data. Their favorable electrical properties, robust binding interactions with viral targets, and attractive pharmacokinetic profiles boost their potential as prospective study subjects. These substances have the potential to be transformed into cutting-edge antiviral therapies that specifically target SARS-CoV-2 Mpro and related coronaviruses.

Antibacterial and anti-biofilm activities of new fluoroquinolone derivatives coupled with nitrogen-based heterocycles

We report the design, synthesis, and antimicrobial evaluation of a series of ciprofloxacin (CP) conjugates coupled with nitrogen-containing heterocycles. In vitro screening of these new hybrid compounds (1–13) against a panel of planktonic bacterial strains highlighted thiazolyl homologs 6 and 7 as the most promising candidates for further investigation. These derivatives demonstrated potent growth-inhibitory activity against various standard and clinical isolates, with minimum inhibitory concentrations (MICs) ranging from 0.05 to 0.4 µg/ml, which are higher or comparable to the reference fluoroquinolone. Both compounds effectively inhibited biofilm formation by selected staphylococci across all tested concentrations (1–8 x MIC), displaying greater efficacy at higher doses compared to CP alone. Notably, conjugate 7 also significantly eradicated existing biofilms formed by S. aureus of various origin. Molecular docking studies revealed that conjugate 7 engages in a broader range of interactions with DNA gyrase and DNA topoisomerase IV than CP, suggesting stronger binding affinity and enhanced flexibility. This may contribute to its potential in overcoming bacterial resistance mechanisms. The above findings indicate compound 7 as a promising candidate for clinical development.

Recent Development of Fluoroquinolone Derivatives as Anticancer Agents.

Cancer is the second leading cause of death in the world following cardiovascular disease. Its treatment, including radiation therapy and surgical removal of the tumour, is based on pharmacotherapy, which prompts a constant search for new and more effective drugs. There are high costs associated with designing, synthesising, and marketing new substances. Drug repositioning is an attractive solution. Fluoroquinolones make up a group of synthetic antibiotics with a broad spectrum of activity in bacterial diseases. Moreover, those compounds are of particular interest to researchers as a result of reports of their antiproliferative effects on the cells of the most lethal cancers. This article presents the current progress in the development of new fluoroquinolone derivatives with potential anticancer and cytotoxic activity, as well as structure-activity relationships, along with possible directions for further development.

SYNTHESIS, CHARACTERIZATION & BIOLOGICAL EVALUATION OF SOME FLUOROQUINOLONE DERIVATIVES AS ANTIMICROBIAL AGENTS

Fluoroquinolones, a class of synthetic antibacterial agents, have gained significant attention due to their broad-spectrum activity against various bacterial pathogens. However, the emergence of resistance to conventional fluoroquinolones underscores the necessity for novel derivatives with enhanced efficacy and reduced resistance profiles. The synthesis of fluoroquinolone derivatives involves structural modifications aimed at improving antimicrobial activity, pharmacokinetic properties, and minimizing adverse effects. Various synthetic routes, including modification of the quinolone core structure, substitution of fluorine atoms, and introduction of diverse functional groups, have been explored to tailor the properties of these derivatives. Characterization techniques such as infrared spectroscopy (IR) has been employed to elucidate the chemical structures and confirm the purity of synthesized compounds. Biological evaluation encompasses in vitro and in vivo studies to assess the antimicrobial activity, cytotoxicity, and pharmacological profiles of fluoroquinolone derivatives. These evaluations provide crucial insights into the therapeutic potential, mechanism of action, and safety profile of novel compounds.

Fluoroquinolone and enoxacin molecules are potential urease inhibitors for treating ureolytic bacterial infections

Urease, a nickel-dependent metalloenzyme, has emerged as a significant therapeutic target due to its role in promoting the pathogenesis of various human health conditions. These include the development of pyelonephritis, urolithiasis, peptic ulcers, hepatic encephalopathy, and gastric ulcers. The currently available treatment involved the usage of strong antibiotics along with proton pump inhibitors to cope with the infection of urease producing bacteria. These conventional treatments are becoming less effective as bacteria are gaining multiple drug resistance. Therefore, there is a crucial need to identify alternative compounds with potential anti-urease activity and minimal side effects. Fluoroquinolones and Enoxacin derivatives offer antimicrobial, anti-inflammatory, antioxidant, anti-diabetic, and anti-urease activities. To improve the chemical diversity of urease inhibitors, different series of fluoroquinolones and Enoxacin derivatives were evaluated against urease and their antioxidant activity was also evaluated. To achieve this objective, in-silico studies were conducted utilizing molecular docking and adsorption, distribution, metabolism, excretion, and toxicology (ADMET) models. These analyses were employed to explore potential binding mechanisms and assess the drug-likeness of the compounds against urease enzymes. The inhibitory effect of docked heterocyclic compounds was also verified in-vitro against urease enzyme. Fluoroquinolones derivatives were found to be active inhibitors at high dose levels but showed minimum inhibition at low concentration. The compound EN from the Enoxacin series exhibited the highest potency as a urease inhibitor, with an IC50 of 45.86 μM, out-performing the standard drug thiourea, which had an IC50 of 52.20 μM. Additionally, compounds NOX-3 and FB-17 from the fluoroquinolone and Enoxacin series demonstrated significant DPPH free radical scavenging activity, with IC50 values of 98.17 μM and 97.98 μM, respectively. These results were comparable to the positive control ascorbic acid, which had an IC50 of 48.15 μM. This study demonstrates that Enoxacin derivatives can be further analyzed as potent urease inhibitors, while both Enoxacin and fluoroquinolone derivatives can be developed into more effective drugs to overcome oxidative stress.

Pseudo-Symmetric Crystallization of Fluoroquinolone Derivatives with a Terpene Moiety

Pseudo-Symmetric Crystallization of Fluoroquinolone Derivatives with a Terpene Moiety

Üç Farklı Kuşak Florokinolon Türevinin Ratlarda Eritrosit Frajilite ve Hematolojik Parametreler Üzerindeki Etkilerinin Araştırılması

Objektive: Fluoroquinolones (FQs) are synthetic broad-spectrum antimicrobial agents derived from nalidixic acid. They are used in the treatment of urinary tract infections, respiratory tract infections, skin infections, digestive system infections, genital infections and other bacterial infections. Although the relationship between FQs and oxidative stress has been demonstrated, their effects on erythrocyte fragility have not been adequately studied. In this study, the effects of three different FQ derivatives (ciprofloxacin (CIP), levofloxacin (LVX) and moxifloxacin (MXF)) on erythrocyte fragility and hematological parameters were investigated in rats at the end of the 1st, 7th and 14th day treatments.
 Material and Method: 72 Wistar albino male rats were divided into 4 groups with 18 rats in each group and sacrificed at three different time points (1st, 7th and 14th days).
 Results: A significant increase in 0.2% sodium chloride (NaCl) concentration erythrocyte fragility value was found in the MXF group on 1st day compared to the control group on 1st day. While the FQ derivatives used in the study did not cause a general change on the erythrocyte and leukocyte parameters, they caused various fluctuations on the platelet parameters such as PCT, PLCR, PDW, MPW and PLT.
 Conclusion: As a further study, it would be beneficial to reveal the reasons for these effects on platelet parameters with more detailed studies.

Synthesis and biological evaluation of 99mTc-tricarbonyl complexes of C-3 carboxy derivatives of fluoroquinolones in infection and tumor animal models

Fluoroquinolones (FQ) are clinically used antibacterial agents. Antibacterial fluoroquinolone derivatives have been shown to exhibit cytotoxic properties in tumor cells. In this work, C3-carboxy fluoroquinolones derivatives were radiolabeled with the diagnostic radionuclide technetium-99 m and were evaluated as infection- and tumor-targeted agents. First, ciprofloxacin and enrofloxacin were converted to 3-hydrazides and then to the respective pyridine hydrazones (L1 and L2). Secondly, 3-carboxamide of enrofloxacin was converted to dipicolylamine (L3), and picolylaminoacetate (L4) tridentate chelators. The respective rhenium-tricarbonyl complexes of L1-L4 were synthesized and characterized by spectroscopic methods and were used as non-radioactive standards to characterize the analogous 99mTc-radiotracers. The 99mTc-tricarbonyl complexes were synthesized and their lipophilicity and stability were evaluated in vitro. The most stable tracers 99mTcL3, 99mTcL4, were incubated with E. coli cells and CT-26 murine colon adenocarcinoma cells to assess their cellular uptake. Also, the 99mTc-tracers were injected in mice, infected with E. coli, as well as in mice, bearing CT-26 tumors.

Dual-Activity Fluoroquinolone-Transportan 10 Conjugates offer alternative Leukemia therapy during Hematopoietic Cell Transplantation.

Hematopoietic cell transplantation (HCT) is often considered a last resort leukemia treatment, fraught with limited success due to microbial infections, a leading cause of mortality in leukemia patients. To address this critical issue, we explored a novel approach by synthesizing antileukemic agents containing antibacterial substances. This innovative strategy involves conjugating fluoroquinolone antibiotics, such as ciprofloxacin (CIP) or levofloxacin (LVX), with the cell-penetrating peptide (CPP) transportan 10 (TP10). Here, we demonstrate that the resultant compounds display promising biological activities in preclinical studies. These novel conjugates not only exhibit potent antimicrobial effects but are also selective against leukemia cells. The cytotoxic mechanism involves rapid disruption of cell membrane asymmetry leading to membrane damage. Importantly, these conjugates penetrated mammalian cells, accumulating within the nuclear membrane without significant effect on cellular architecture or mitochondrial function. Molecular simulations elucidated the aggregation tendencies of TP10 conjugates within lipid bilayers, resulting in membrane disruption and permeabilization. Moreover, mass spectrometry analysis confirmed efficient reduction of disulfide bonds within TP10 conjugates, facilitating release and activation of the fluoroquinolone derivatives. Intriguingly, these compounds inhibited human topoisomerases, setting them apart from traditional fluoroquinolones. Remarkably, TP10 conjugates generated lower intracellular levels of reactive oxygen species (ROS) compared to CIP and LVX. The combination of antibacterial and antileukemic properties, coupled with selective cytostatic effects and minimal toxicity towards healthy cells, positions TP10 derivatives as promising candidates for innovative therapeutic approaches in the context of antileukemic HCT. This study highlights their potential in search of more effective leukemia treatments. Significance Statement Fluoroquinolones are commonly used antibiotics, while TP10 is a CPP with anticancer properties. In HCT, microbial infections are the primary cause of illness and death. Combining TP10 with fluoroquinolones enhanced their effects on different cell types. The dual pharmacological action of these conjugates offers a promising proof-of-concept solution for leukemic patients undergoing HCT. Strategically designed therapeutics, incorporating CPPs with antibacterial properties, have the potential to reduce microbial infections in the treatment of malignancies.

Evaluation of mechanical features and antibacterial potential of fluoroquinolone against β-ketoacyl-ACP synthases (FabB, FabF & FabH) via computational approaches

The synthesis of fatty acids, which are essential for the growth and survival of bacterial cells, is catalyzed by beta-keto acyl-ACP synthase I-III. Due to the significant differences between the bacterial ACP synthase enzyme and the mammalian enzyme, it may serve as a viable target for the development of potent anti-bacterial medications. In this study, a sophisticated molecular docking strategy was employed to target all three KAS enzymes. Initially, 1000 fluoroquinolone derivatives were obtained from PubChem database, along with the commonly used ciprofloxacin, and subjected to virtual screening against FabH, FabB, and FabF, respectively. Subsequently, molecular dynamics (MD) simulations were conducted to confirm the stability and reliability of the generated conformations. The compounds 155813629, 142486676, and 155567217 were found to exhibit potential molecular interactions against FabH, FabB, and FabF, respectively, with docking scores of −9.9, −8.9, and −9.9 kcal/mol. These scores outperformed the docking score of standard ciprofloxacin. Furthermore, MD simulations were used to assess the dynamic nature of molecular interactions in both physiological and dynamic settings. Throughout the simulated trajectory, all three complexes displayed favorable stability patterns. The findings of this investigation suggest that fluoroquinolone derivatives may serve as highly effective and selective inhibitors of the KAS enzyme.

Prospects for use of combined antibacterial drugs. Simprazol®: When whole is greater than sum

Today, in the pharmaceutical industry, many manufacturers produce so-called combined drugs containing 2 or 3 or more active ingredients. There are many reviews and studies in the world literature proving that most combinations, in contrast to sequential administration, often have a more pronounced synergistic effect of combined drugs. The use of such therapy increases patient compliance, while at the same time causing positive pharmacokinetic and other effects inherent in the combination, providing the clinician with new opportunities in the treatment of infections. Although the combination of fluoroquinolone and fixed-dose nitroimidazole derivatives is not as widely used in clinical practice, we present a review of Simprazole®, a combination of ciprofloxacin and ornidazole, analyzing the available data on clinical use and possible prospects that new drug.

Interaction between a fluoroquinolone derivative KG022 and RNAs: Effect of base pairs 3' adjacent to the bulged residues.

RNA-targeted small molecules are a promising modality in drug discovery. Recently, we found that a fluoroquinolone derivative, KG022, can bind to RNAs with bulged C or G. To clarify the RNA specificity of KG022, we analyzed the effect of the base pair located at the 3'side of the bulged residue. It was found that KG022 prefers G-C and A-U base pairs at the 3'side. Solution structures of the complexes of KG022 with the four RNA molecules with bulged C or G and G-C or A-U base pairs at the 3'side of the bulged residue were determined to find that the fluoroquinolone moiety is located between two purine bases, and this may be the mechanism of the specificity. This work provides an important example of the specificity of RNA-targeted small molecules.

Novel Gatifloxacin3-Carboxamide Derivatives as Anti-Tumor Agents: Synthesis, Enantioseparation, and Molecular Docking

Background:: The drug's affinity to the identified target (protein/enzyme) is a critical characteristic in the development of a novel drug. Fluoroquinolone derivatives with a carboxylic group change have improved antimicrobial and anticancer activity while maintaining antibacterial activity similar to parent drugs. Aim:: The rationale upon which synthesis of the new compounds, evaluation of their anticancer activity with in silico study, and suggestion of their mechanism of action is presented in this paper. Methods:: This part describes the practical procedures used for the synthesis of four new gatifloxacin 3-carboxamide derivative, with their spectral data (UV-vis, IR, and 1H-NMR). The enantiosaparation and docking studies are presented and discussed. Results:: Four gatifloxacin 3-carboxamide derivatives were enantioseparated using a high-performance liquid chromatography approach using two distinct polysaccharide-based chiral stationary phases (CSPs). The baseline enantioseparation of all derivatives evaluated in this study was achieved using both coated and immobilized amylose columns. In silico molecular docking study, revealed that all compounds showed good docking score. Conclusion:: The novel Fluoroquinolone caboxamides derivatives could be repositioned as DNA topoisomerase II inhibitors, allowing them to be employed as anticancer agents, according to our in silico study. Experiments in vitro and in vivo are required to confirm their efficacy.

Fluoroquinolone Derivatives in the Treatment of Mycobacterium tuberculosis Infection.

Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of multidrug-resistant tuberculosis (MDR TB) cases poses an emergent public health threat. Fluoroquinolones are commonly used in the treatment of both MDR TB and drug-sensitive tuberculosis patients who are intolerant to first-line antitubercular agents. Unfortunately, these drugs have mild side effects, relevant to the prolonged treatment regimens and diminished bioavailability due to binding of metal ions. Moreover, the resistance to fluoroquinolones is also on the rise, a characteristic of extensively drug-resistant TB (XDR TB). Here, we developed esters as prodrugs of the fluoroquinolones levofloxacin and ciprofloxacin, with long-chain fatty alcohols. Both the alcohols and the quinolone have previously shown antimycobacterial activity and the aim was to develop esters with improved lipophilicity and capable of delivering the free acid inside mycobacterial cells. The carboxylic acid group of fluoroquinolones is essential to the mode of action but is also responsible for many of its side effects and metal-chelating properties. The synthesis, stability in biological media, and antibacterial activity were evaluated, the latter not only against Mycobacterium tuberculosis but also against other clinically relevant bacterial species, since the parent compounds display a broad spectrum of activity. The biological results show a reduction in the antitubercular activity of the synthesized derivatives, probably due to deficient activation of the ester prodrug. Despite this, it was found that the derivatives exhibit bioactivity against other fluoroquinolone-resistant bacteria, indicating a different mode of action and suggesting that it may be worthwhile to research further modifications to the carboxylic acid group. This might lead to new compounds that are efficient against resistant strains. This idea that the compounds may act by a different mechanism of action was further supported by a brief computer investigation that demonstrated the potential lack of selectivity of the esters to the fluoroquinolone target.

Treatment of Bovine Leptospirosis with Enrofloxacin HCl 2H2O (Enro-C): A Clinical Trial.

Simple SummaryUnlike standard enrofloxacin, its crystal solvate enrofloxacin HCl-2H2O (enro-C) exhibits favorable pharmacokinetics and PK/PD ratios compatible with its use as a treatment during the clinical phase of leptospirosis in cattle. Hence, a clinical trial was conducted in cattle located either in the highlands (HL) or the tropics (TL). A high dose of 15 mg/kg day IM of enro-C administered over 5 days was compared against the conventional treatment with streptomycin/penicillin-G. The cows treated with enro-C became PCR negative: 87.5% and 78.94% on day 5, and 92.85% and 94.73% on day 28 (in the HL and TL, respectively). For streptomycin/penicillin-G, the same values were 65.45% and 70.90% on day 5 and 73.68% in both scenarios on day 28. In both groups, the microagglutination titers dropped on day 28, and gestation rates were statistically indistinguishable between the groups. This is the first report of successful treatment with fluoroquinolone in treating bovine leptospirosis.Pharmacokinetics/pharmacodynamics ratios of enrofloxacin HCl-2H2O (enro-C) in cows to treat bovine leptospirosis prompted this clinical trial in the highlands (HL) and the tropics (TL) in Mexico. In the HL, 111 Holstein-Friesian cows were included and 38 F1 Zebu–Holstein/Friesians in the TL. Affected cows were randomly divided into two treatment groups, both in the HL and TL. PCR and MAT tests were performed before and after treatment. Treatments in both groups were administered for 5 d with either IM injections of enro-C or streptomycin/penicillin-G. Reproductive performance data were gathered for 90 d. The cows treated with enro-C became PCR negative: 87.5% and 78.94% on day 5, 92.85% and 94.73% on day 28 (in the HL and TL, respectively). For streptomycin/penicillin-G, the same values were 65.45% and 70.90% on day 5, and 73.68% twice on day 28 in the HL and TL, respectively. In both groups and geographical settings, the MAT titers dropped on day 28 but remained above reference values usually considered negative. The gestation rates were: 86.53% and 79.06% and 88.88% and 87.5% for the HL and TL, either with enro-C or streptomycin/penicillin-G, respectively. This is the first report of successful treatment with a fluoroquinolone derivative in treating bovine leptospirosis with a high bacteriological cure rate.

Study of Antimicrobial Effect of a New Fluoroquinolone Derivative Against Pathogenic Bacteria in Planktonic Form and Biofilm

Study of Antimicrobial Effect of a New Fluoroquinolone Derivative Against Pathogenic Bacteria in Planktonic Form and Biofilm

Exploration of Spirocyclic Derivatives of Ciprofloxacin as Antibacterial Agents.

The previously reported as well as newly synthesized derivatives of the 1-oxa-9-azaspiro[5.5]undecane were employed in the synthesis of thirty-six derivatives of ciprofloxacin using commercially available 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and the literature protocol involving the preparation of boron chelate complex to facilitate nucleophilic aromatic substitution. All new fluoroquinolone derivatives were tested against two gram-positive as well as three gram-negative strains of bacteria. With the activity spectrum of the new derivatives being substantially narrower than that of ciprofloxacin, compounds were distinctly active against two of the five strains: gram-negative Acinetobacter baumannii 987® and gram-positive Bacillus cereus 138®. Towards these two strains, a large group of compounds displayed equal or higher potency than ciprofloxacin.

Bio-Enhanced Degradation Strategies for Fluoroquinolones in the Sewage Sludge Composting Stage: Molecular Modification and Resistance Gene Regulation.

The molecular/protein–protein docking and the index normalization method assisted by the entropy weight method were used to quantitatively evaluate the biodegradability of fluoroquinolones (FQs) under different biodegradation systems. Four biodegradability three-dimensional quantitative structure–activity relationship (3D-QSAR) models of FQs were constructed to design FQ derivatives with improved biodegradability. Through the evaluation of the environmental friendliness and functional properties, the FQ derivatives with high biodegradability, improved functionality, and environmental friendliness were screened. Moreover, four bio-enhanced degradation scenarios of FQs were set up according to the different temperatures and carbon–nitrogen ratio (C/N) in the sewage sludge composting stage, and the molecular dynamic (MD) simulation assisted by protein–protein docking was used to screen the external environmental factors that promote the degradation of FQs by thermophilic bacteria or group under different scenarios. Finally, MD simulation assisted by sampling method was used to validate and screen the application scheme of field measures to enhance the expression of antibacterial resistance of FQ derivatives in an agricultural soil environment after activated sludge land use. This study aims to provide theoretical support for the development of highly biodegradable FQ derivatives and the mitigation of potential risks that FQs may pose to the environment and humans through the food chain.

Dithienylethene-Bridged Fluoroquinolone Derivatives for Imaging-Guided Reversible Control of Antibacterial Activity.

The emerging field of photopharmacology has offered a promising alternative to guard against the bacterial resistance by effectively avoiding antibiotic accumulation in the body or environment. However, the degradation, toxicity, and thermal reversibility have always been an ongoing concern for potential applications of azobenzene-based photopharmacology. Developing novel photopharmacological agents based on a more matched switch is highly in demand and remains a major challenge. Herein, two novel dithienylethene-bridged dual-fluoroquinolone derivatives have been developed by introducing two fluoroquinolone drugs into both ends of the dithienylethene (DTE) switch, in which the fluoroquinolone acts as a fluorophore except for the pharmacodynamic component. For comparison, two monofluoroquinolone-DTE hybrids were also prepared by a similar strategy. As expected, these resultant DTE-based antibacterial agents displayed efficient photochromism and fluorescence switching behavior in dimethyl sulfoxide. Moreover, improved antibacterial activities compared to those of monofluoroquinolone derivatives and a maximum fourfold active difference against Escherichia coli (E. coli) for open and closed isomers and photoswitchable bacterial imaging for Staphylococcus aureus and E. coli were observed. The molecular docking to DNA gyrase gave a rationale for the discrepancies in antibacterial activity for both isomers. Therefore, these fluoroquinolone derivatives can act as interesting imaging-guided photopharmacological agents for further in vivo studies.

Synthesis and antimycobacterial evaluation of fluoroquinolones derivatives coupled with isoprenyl moiety at the C-7 position

Synthesis and antimycobacterial evaluation of fluoroquinolones derivatives coupled with isoprenyl moiety at the C-7 position