Quinolone Compounds Research Articles

A method for simultaneously and accurately quantify seven quinolones in matrix reference materials by HPLC-MS

Reference materials (RM) are commonly employed in analytical chemistry for tasks such as instrument calibration, validation of analytical methods and quality control. Determining the values of target drugs in the matrix is a key step in the development of matrix reference materials. However, there is almost no sharing of the certification methodologies for the development of RM. Hence, a detailed method was established for the value determination of seven quinolones in minced fish matrix, which was the candidate materials for preparing matrix reference materials. Target analysis of quinolone drugs in complex matrix was performed by “quick, easy, cheap, effective, rugged and safe” (QuEChERS) extraction and high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS). The accuracy, precision, and sensitivity of this method has been thoroughly validated, which provided a robust analytical tool for the accurate quantification of quinolones in quality control samples and actual samples with a detection limit of 0.5–0.6 μg/kg and a quantification limit of 1 μg/kg. The actual samples prepared by three different spiking methods was determined, the outstanding performance show that this method contributing significantly to the development of matrix reference materials in aquatic products, which can be used as a template for the determination of other quinolone compounds in minced fish matrix. This work can not only provide reference for the development of matrix reference materials, but also promote the development of metrology.

Structural and mechanistic insights into Quinolone Synthase to address its functional promiscuity

Quinolone synthase from Aegle marmelos (AmQNS) is a type III polyketide synthase that yields therapeutically effective quinolone and acridone compounds. Addressing the structural and molecular underpinnings of AmQNS and its substrate interaction in terms of its high selectivity and specificity can aid in the development of numerous novel compounds. This paper presents a high-resolution AmQNS crystal structure and explains its mechanistic role in synthetic selectivity. Additionally, we provide a model framework to comprehend structural constraints on ketide insertion and postulate that AmQNS’s steric and electrostatic selectivity plays a role in its ability to bind to various core substrates, resulting in its synthetic diversity. AmQNS prefers quinolone synthesis and can accommodate large substrates because of its wide active site entrance. However, our research suggests that acridone is exclusively synthesized in the presence of high malonyl-CoA concentrations. Potential implications of functionally relevant residue mutations were also investigated, which will assist in harnessing the benefits of mutations for targeted polyketide production. The pharmaceutical industry stands to gain from these findings as they expand the pool of potential drug candidates, and these methodologies can also be applied to additional promising enzymes.

Tractable Quinolone Hydrazides Exhibiting Sub-Micromolar and Broad Spectrum Antitrypanosomal Activities.

Nagana and Human African Trypanosomiasis (HAT), caused by (sub)species of Trypanosoma, are diseases that impede human and animal health, and economic growth in Africa. The few drugs available have drawbacks including suboptimal efficacy, adverse effects, drug resistance, and difficult routes of administration. New drugs are needed. A series of 20 novel quinolone compounds with affordable synthetic routes was made and evaluated in vitro against Trypanosoma brucei and HEK293 cells. Of the 20 compounds, 12 had sub-micromolar potencies against the parasite (EC50 values=0.051-0.57 μM), and most were non-toxic to HEK293 cells (CC50 values>5 μM). Two of the most potent compounds presented sub-micromolar activities against other trypanosome (sub)species (T. cruzi and T. b. rhodesiense). Although aqueous solubility is poor, both compounds possess good logD values (2-3), and either robust or poor microsomal stability profiles. These varying attributes will be addressed in future reports.

Photo-induced synthesis of fluoroalkylated quinolinones via an iron-catalyzed LMCT decarboxylation process

A general synthesis of fluoroalkylated quinolone compounds using a visible-light-induced iron catalyzed LMCT method is reported herein.

Synthesis and Anticancer Activity of 1‐(Ethyl/Methyl)‐7‐(p‐Methoxybenzyl Amino) and 7‐Amino‐6‐Fluoroquinolone‐Boron Difluoride Complexes

AbstractNovel 1‐(ethyl/methyl)‐7‐(p‐methoxybenzyl amino) and 7‐amino‐6‐fluoroquinolone‐boron difluoride complexes were synthesized, and their biological activity was studied, comparing the influence of the nature of 7‐substituent as well as N‐1 substituent. The quinolone compounds were characterized by IR, UV‐Vis, 1H, 13C{1H} and 19F{1H} NMR, and mass spectrometry. The antiproliferative effect of the new fluoroquinolone‐boron complexes in breast cancer (BC) derived cell lines MCF‐7 and SKBR‐3 was investigated. Compounds 9 b and 9 a showed antiproliferative in MCF‐7 cells, and 9 b, 11 b, 9 a, 7 a, 7b and 8 a showed similar effects in SKBR‐3 cells. Derivatives with p‐methoxybenzyl amino moieties at C‐7 and an ethyl or methyl group at N‐1 in the fluoroquinolone ring (9 a and 9 b) were the more efficient in both breast cancer cell lines. In addition, an 8‐nitro group to the fluoroquinolone (11 b) improved activity against SKBR‐3 cell proliferation. These compounds represent potential drug candidates for breast cancer treatment.

Comprehensive study on the potential environmental risk of temporal antibiotic usage through wastewater discharges

Antibiotic residues can reach aquatic ecosystems through urban wastewater discharges, posing an ecotoxicological risk for aquatic organisms and favoring the development of bacterial resistance. To assess the emission rate and hazardousness of these compounds, it is important to carry out periodic chemical monitoring campaigns that provide information regarding the actual performance of wastewater treatment plants (WWTPs) and the potential impact of the treated wastewater in the aquatic environment. In this study, 18 of the most widely consumed antibiotics in Spain were determined by liquid chromatography-tandem mass spectrometry in both influent (IWW) and effluent wastewater (EWW) samples collected over four seasons along 2021–2022. Eleven antibiotics were detected in EWW with azithromycin, ciprofloxacin and levofloxacin showing the highest concentration levels (around 2 μg L−1 of azithromycin and 0.4 μg L−1 of quinolone compounds). Data showed that only 4 out of the 11 compounds were removed by more than 50 % in the WWTP, with sulfamethoxazole standing out with an average removal efficiency >80 %. The risk that treated water could pose to the aquatic environment was also assessed, with 6 compounds indicating a potential environmental risk by exceeding established ecotoxicological and resistance thresholds. Based on the risk assessment, the WWTP removal efficiency required to reduce such risk for antibiotics was estimated. In addition, pooled wastewater samples were screened by LC coupled to high resolution mass spectrometry with ion mobility separation, searching for metabolites and transformation products of the antibiotics investigated to widen future research. Studies like this are crucial to map the impact of antibiotic pollution and to provide the basis for designing water quality and risk prevention monitoring programs.

Quinolone-3-amidoalkanol: A New Class of Potent and Broad-Spectrum Antimicrobial Agent.

Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-positive and -negative bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.

Isolation of rice endophytic bacterial strain VY81 and study on its bioactive compound antagonizing the phytopathogen Dickeya zeae

The bacterial communities performing endophytic lifestyle have been proven to possess a number of characteristics useful to host plants and thus are considered as “plant probiotics”. Many probiotic bacteria were reported for antagonism against different plant pathogens, including bacteria, fungi, and nematodes. The use of endophytic bacteria as biocontrol agents would have great potentials, allowing reducing the use of agrochemicals and thus support a sustainable agriculture. &#x0D; In this study, endophytic bacteria isolated from rice plants of IR4625 cultivar from Long An province, Vietnam were used for screening strains that have antagonistic activity against Dickeya zeae (Dz), the bacterium causing foot rot disease. The rice plants had foot rot disease symptoms, i.e. dark-brown foot with odor smell typical for bacterial infection. Strain VY81 was isolated from a surface sterilized rice stem sample adjacent to the foot rot area. The crude extract of strain VY81 showed significant antagonistic activity against Dz, with the inhibition zone of 14,25 mm ± 1,06 in diameter. Strain VY81 produced the compound antagonizing Dz at maximal level after 48 h cultivated in TSB medium. The activity was found mainly in the culture broth, just a small part was found intracellularly. The bioactive compound antagonizing D. zeae produced by strain VY81 was purified by HPLC and analyzed by mass spectrometry and NMR spectroscopy. The compound was identified as a quinoline alkaloid, the chemical formula is C17H21ON with chemical name 2-(2-heptenyl)-3-methyl-4(1H)-quinolone. Comparative analyses of the 16S rDNA gene sequence revealed that strain VY81 belonged to the genus Burkholderia, most closely related to Burkholderia cepacia (99,77% sequence homology). The 16S rDNA sequence of strain VY81 was deposited at GenBank under accession number MW056196. Strain VY81 and its quinolone compound would have application potential for development of biocontrol product against the foot rot disease caused by Dickeya zeae.

Quinolone: a versatile therapeutic compound class.

The discovery of nalidixic acid is one pinnacle in medicinal chemistry, which opened a new area of research that has led to the discovery of several life-saving antimicrobial agents (generally referred to as fluoroquinolones) for over decades. Although fluoroquinolones are frequently encountered in the literature, the utility of quinolone compounds extends far beyond the applications of fluoroquinolones. Quinolone-based compounds have been reported for activity against malaria, tuberculosis, fungal and helminth infections, etc. Hence, the quinolone scaffold is of great interest to several researchers in diverse disciplines. This article highlights the versatility of the quinolone pharmacophore as a therapeutic agent beyond the fluoroquinolone profile.

In-silico Investigations of quinine and quinidine as potential Inhibitors of AKR1B1 and AKR1B10: Functional and structural characterization.

The aberrant expression of aldo keto reductases (AKR1B1 & AKR1B10) has been extensively studied in different types of cancer especially the colon cancer but a very few studies have yet been reported regarding the discovery of inhibitors for the treatment of colon cancer by targeting these isozymes. Therefore, there is a need of selective inhibitors of both targets for the eradication of colon cancer. Currently, the study is focused on the exploration of two quinolone compounds i.e., (S)-(6-Methoxyquinolin-4-yl)[(1S,2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinidine) and (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (Quinine) as the potential inhibitors of AKR1B1 and AKR1B10 via detailed in-silico approach. The structural properties including vibrational frequencies, dipole moment, polarizability and the optimization energies were estimated using density functional theory (DFT) calculations; where both compounds were found chemically reactive. After that, the optimized structures were used for the molecular docking studies and here quinidine was found more selective towards AKR1B1 and quinine exhibited maximum inhibition of AKR1B10. The results of molecular docking studies were validated by molecular dynamics simulations which provided the deep insight of stability of protein ligand complex. At the end, the ADMET properties were determined to demonstrate the druglikeness properties of both selected compounds. These findings suggested further exploration of both compounds at molecular level using different in-vivo and in-vitro approaches that will lead to the designing of potential inhibitor of AKR1B1/AKR1B10 for curing colon cancer and related malignancies.

Correction for Oka et al., "In Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficile".

Correction for Oka et al., "In Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficile".

Emerging quinoline- and quinolone-based antibiotics in the light of epidemics.

Pandemics are large-scale outbreaks of infectious disease that can greatly increase morbidity and mortality all the globe. Since past 1990 till twentieth century, these infectious diseases have been major threat all over the globe associated with poor hygiene and sanitation. In light of these epidemics, researches have gained enormous rise in the developing the potential therapeutic treatment. Thus, revolutionized antibiotics have led to the near eradication of such ailments. Around 50million prescription of antibiotics written in US per year according to center for disease control and prevention (CDC) report. There is a wide range of antibiotics available which differ in their usage and their mechanism of action. Among these quinoline and quinolone class of antibiotics get attention as they show tremendous potential in fighting the epidemics. Quinoline and quinolone comprise of two rings along with substitutions at different positions which is synthetically obtained by structural modifications of quinine. Quinoline and quinolone antibiotics exhibit extensive activities approved by FDA in the treatment of the several ailments such as gastrointestinal infections, urinary tract infections, prostate inflammation, malaria, gonorrhea, skin infection, colorectal cancer, respiratory tract infections. These are active against both gram-negative and gram-positive bacteria. This basic core of quinoline and quinolone is vital due to its capability of targeting the pathogen causing disease and beneficial in treating the infectious disease. They inhibit the synthesis of nucleic acid of bacteria which results in the rupture of bacterial chromosome due to the interruption of enzymes such as DNA gyrase and topoisomerase IV. There are various quinoline and quinolone compounds that are synthetically derived by applying different synthesis approaches which show a wide range of pharmacological activities in several diseases. The most commonly used are fluoro, chloro, and hydroxychloro derivatives of quinoline and quinolone. These compounds are helpful in the treatment of numerous epidemics as a chief and combination therapy. These quinoline and quinolone pharmacophore fascinate the interest of researchers as they inhibit the entry of virus in host cell and cease its replication by blocking the host receptor glycosylation and proteolytic processing. They act as immune modulator by inhibiting autophagy and reduction of both lysosomal activity and production of cytokine. Therefore, quinoline and quinolone derivatives attain significance in area of research and treatment of various life-threatening epidemics such as SARS, Zika virus, Ebola virus, dengue, and COVID-19 (currently). In this chapter, the research and advancements of quinoline- and quinolone-based antibiotics in epidemic management are briefly discussed.

Quinolone Signals Related to Pseudomonas Quinolone Signal-Quorum Sensing Inhibits the Predatory Activity of Bdellovibrio bacteriovorus.

Bdellovibrio bacteriovorus is one of the predatory bacteria; therefore, it can act as a novel “living antibiotic,” unlike the current antibiotics. Here the predation of Escherichia coli by B. bacteriovorus was inhibited in the presence of Pseudomonas aeruginosa. This study investigated whether P. aeruginosa-induced predation inhibition is associated with bacterial quorum sensing (QS). Each las, rhl, or pqs QS mutant in P. aeruginosa was used to check the predatory activity of E. coli cells using B. bacteriovorus. As a result, the predatory activity of B. bacteriovorus increased in a mutant pqs QS system, whereas wild-type PA14 inhibited the predatory activity. Moreover, the addition of 4-hydroxy-2-heptylquinoline (HHQ) or the analog triggered the low predatory activity of B. bacteriovorus and killed B. bacteriovorus cells. Therefore, a defensive action of P. aeruginosa against B. bacteriovorus is activated by the pqs QS system, which produces some quinolone compounds such as HHQ.

Raja 42, a novel gamma lactam compound, is effective against Clostridioides difficile.

Clostridioides difficile infection (CDI) is the primary cause of hospital-acquired diarrhea, and responsible for over 500,000 enteric infections a year in the United States alone. Although most patients with CDI are successfully treated with metronidazole or vancomycin, the high rate of recurrence is still a serious problem, in which case these antibiotics are usually not very effective. The primary objective of this research is to develop a potentially effective therapeutic agent against C. difficile that are resistant to metronidazole or vancomycin. The susceptibility to metronidazole and vancomycin was examined with 194 C. difficile clinical isolates. Sixty of these isolates chosen based on a variety of criteria were examined for their susceptibility against the 4-chloro-1-piperidin-1ylmethyl-1H-indole-2,3-dione compound (Raja 42), a novel isatin–benzothiazole analogue containing a gamma-lactam structure, as we previously found that this novel compound is effective against a variety of different bacteria. Most of the 60 isolates were resistant to ceftriaxone and ciprofloxacin, raising the possibility that they might have been exposed previously to these or structurally similar antibiotics (e.g., β-lactam and quinolone compounds). Among the isolates, 48 (80%) and 54 (90%) were susceptible to metronidazole and vancomycin, respectively. Raja 42 was found to be effective against most of the isolates, especially so against metronidazole-resistant C. difficile. Most importantly, five isolates that show resistance to metronidazole and vancomycin were sensitive to Raja 42. Thus, Raja 42, a gamma lactam antibiotic, has the potential to effectively control C. difficile strains that are resistant to metronidazole and vancomycin.

Neuroprotective effects of 2-heptyl-3-hydroxy-4-quinolone in HT22 mouse hippocampal neuronal cells

The neuroprotective activity of 2-heptyl-3-hydroxy-4(1H)-quinolone (compound 1) was evaluated using the neurotoxicity of glutamate in the HT22 cell line. Compound 1, known as a signal molecule of the bacterial quorum-sensing system, protects neuronal cells from glutamate-induced neurotoxicity by inhibiting cellular Ca2+ uptake and glutamate-triggered ROS accumulation. MAPK signaling pathway inhibition by compound 1 was evaluated by immunoblotting the phosphorylation status of the proteins. Furthermore, pro-apoptotic protein levels and AIF translocation to the nucleus were found to be reduced by compound 1. In conclusion, compound 1 showed neuroprotective effects by inhibiting apoptotic neuronal cell death.

A New Scalable Synthesis of ELQ-300, ELQ-316, and other Antiparasitic Quinolones.

The Endochin-Like Quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised that lowers costs and is amenable to large scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad-Limpach reaction to produce 3-substituted 4(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first described to be truly amenable to industrial scale production, is relatively short (5 reaction steps), does not require palladium, chromatographic separation or protecting group chemistry, and may be performed without high vacuum distillation.

Upregulation of wild-type p53 by small molecule-induced elevation of NQO1 in non-small cell lung cancer cells.

The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms, and its reactivation represents an attractive therapeutic strategy for cancers. Here, we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer (NSCLC) cells which express wild type (wt) p53, in contract to its much weaker cytotoxicity on cells with mutant p53. RYL-687 upregulated p53 in cells with wt but not mutant p53, and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound. RYL-687 induced production of reactive oxygen species (ROS) and upregulation of Nrf2, leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1 (NQO1) that can protect p53 by inhibiting its degradation by 20S proteasome. RYL-687 bound NQO1, facilitating the physical interaction between NQO1 and p53. NQO1 was required for RYL-687-induced p53 accumulation, because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine, drastically suppressed RYL-687-induced p53 upregulation. Moreover, a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model. These data indicate that targeting NQO1 is a rational strategy to reactivate p53, and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.

In Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficile.

OPS-2071 is a novel quinolone antibacterial agent characterized by low oral absorption that reduces the risk of adverse events typical of fluoroquinolone class antibiotics. The in vitro and in vivo antibacterial activities of OPS-2071 against Clostridioides difficile were evaluated in comparison to vancomycin and fidaxomicin. OPS-2071 exhibited potent antibacterial activity against 54 clinically isolated C. difficile strains with a MIC of 0.125 μg/ml (MIC50) and 0.5 μg/ml (MIC90), making it more active than vancomycin on a concentration basis (MIC50, 2 μg/ml; MIC90, 4 μg/ml) and comparable to fidaxomicin (MIC50, 0.063 μg/ml; MIC90, 8 μg/ml). OPS-2071 showed equally potent antibacterial activity against both hypervirulent and nonhypervirulent strains, while a significant difference in susceptibility to fidaxomicin was observed. Spontaneous resistance to OPS-2071 and vancomycin was not observed; however, resistance to fidaxomicin was observed at 4× MIC. The mutant prevention concentration of OPS-2071 was 16-fold lower than those of fidaxomicin and vancomycin, and the postantibiotic effect of OPS-2071 was longer than those of fidaxomicin and vancomycin. Also, OPS-2071 showed low systemic exposure, with OPS-2071 having 2.9% oral bioavailability at 1 mg/kg in rats. Furthermore, OPS-2071 showed significant in vivo efficacy at 0.0313 mg/kg/day (50% effective doses), 39.0-fold and 52.1-fold lower than those of vancomycin and fidaxomicin, respectively, in a hamster model of C. difficile infection. OPS-2071 has the potential to become a new therapeutic option for treating C. difficile infection.

Easy-To-Access Quinolone Derivatives Exhibiting Antibacterial and Anti-Parasitic Activities.

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24–31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4–20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.

Design, Synthesis, Molecular Docking and Antibacterial Screening of some Quinolone Compounds

Some 6,8-dichloro-quinolone compounds were designed and synthesized; by comparing with 6-fluoro-8-chloro-quinolone compounds, the influence of the nature of the halogen atom from six position of the quinolone ring on the molecular properties and on the antimicrobial activity was studied. The DFT/B3LYP/6-311G* level of basis set was used for the computation of molecular structure of optimized compounds. The calculations of characteristics and molecular properties were performed using Spartan�14 Software from Wavefunction, Inc. Irvine, CA. The HOMO-LUMO energies and orbitals, global reactivity descriptors, various thermodynamic parameters, and dipole moment (i) were calculated to determine the molecular properties of quinolone compounds. Molecular docking studies were realized to identify and visualize the most likely interaction ligand (quinolone/fluoroquinolone compounds) with the protein receptor. The score and hydrogen bonds formed with the amino acids from group interaction atoms are used to predict the binding modes, the binding affinities, and the orientation of the docked quinolone/fluoroquinolone derivatives in the active site of the protein receptor. The protein-ligand complex was realized based on the X-ray structure of Bacillus cereus (PDB ID: 1VEN) using CLC Drug Discovery Workbench 2.4 software. The quinolone compounds were characterized by physical-chemical methods (elemental analysis, IR spectral analysis, 1H-NMR, 13C-NMR spectra, UV-Vis, thin layer chromatography) and by antimicrobial activity against some Gram-positive and Gram-negative microorganisms: Staphylococcus aureus, Bacillus cereus, Bacillus subtilis, Micrococcus luteus, Escherichia coli and Pseudomonas aeruginosa.