Showing papers on "Quinolone published in 2015"

Mechanisms of drug resistance: quinolone resistance.

Abstract: Quinolone antimicrobials are synthetic and widely used in clinical medicine Resistance emerged with clinical use and became common in some bacterial pathogens Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s) These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes Mutations of both types can accumulate with selection pressure and produce highly resistant strains Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones Thus, the bacterial quinolone resistance armamentarium is large

Design, Synthesis, and Antimicrobial Evaluation of Novel Quinolone Imidazoles and Interactions with MRSA DNA.

Abstract: A novel series of quinolone imidazoles as new type of antimicrobial agents were synthesized. Most compounds exhibited good bioactivities especially against MRSA even superior to reference drugs. They induced bacterial resistance more slowly than clinical drugs and gave low cytotoxicity to human cells. The pKa values of these compounds showed appropriate ranges to pharmacokinetic behaviors. The interactions between compound 8b, Cu(2+) ion, and MRSA DNA revealed that compound 8b could intercalate into DNA through copper ion bridge to form a steady 8b-Cu(2+) -DNA ternary complex which might further block DNA replication to exert the powerful bioactivities. Study of compound 8b with human serum albumin indicated that compound 8b could be effectively stored and carried by human serum albumin.

Safety issues and drug–drug interactions with commonly used quinolones

Abstract: Introduction: Quinolones are widely used antimicrobials with good efficacy and favourable safety. Recently, forms of quinolone toxicity such as peripheral neuropathy, retinal detachment or QTc-prolongation have attracted attention.Areas covered: Data on different aspects of direct quinolone toxicity are reviewed and consider risk factors and predisposing structural properties. Indirect forms of quinolone toxicity such as Clostridium difficile infections or adverse reactions associated with drug–drug interactions are also discussed. Finally, the role of transporters in the pharmacokinetics of these antimicrobials and their utilisation in critically ill patients are illustrated. A MEDLINE PubMed search for articles published in English from January 1960 to June 2014 was completed using the terms: quinolone, quinolone-induced toxicity, quinolone pharmacokinetics, quinolone and critically ill, drug–drug interactions.Expert opinion: Quinolones exhibit an important component of the antibiotic arsenal. Although ...

Design, synthesis, and antibacterial evaluation of novel azolylthioether quinolones as MRSA DNA intercalators

Abstract: A series of azolylthioetherquinolones was synthesized and characterized by NMR, IR, MS and HRMSspectroscopy. All the newly prepared compounds were screened for their antimicrobial activities. Bioactive assay manifested that most of the azolylthioether quinolones exhibited good antimicrobial activities. Especially, imidazolylthioether quinolone 4e displayed remarkable anti-MRSA and anti-P. aeruginosa efficacies with low MIC values of 0.25 μg mL−1, even superior to reference drugs. They induced bacterial resistance more slowly than clinical drugs. Molecular docking study indicated strong binding interactions of compound 4e with topoisomerase IV–DNA complex, which correlated with the inhibitory effect. The preliminarily interactive investigation of compound 4e with genomic DNA isolated from MRSA revealed that compound 4e could intercalate into MRSA DNA through a copper ion bridge to form a steady 4e–Cu2+–DNA ternary complex which might further block DNA replication to exert the powerful bioactivities.

Development of a Pefloxacin Disk Diffusion Method for Detection of Fluoroquinolone-Resistant Salmonella enterica

Abstract: Fluoroquinolones (FQs) are among the drugs of choice for treatment of Salmonella infections. However, fluoroquinolone resistance is increasing in Salmonella due to chromosomal mutations in the quinolone resistance-determining regions (QRDRs) of the topoisomerase genes gyrA, gyrB, parC, and parE and/or plasmid-mediated quinolone resistance (PMQR) mechanisms including qnr variants, aac(6′)-Ib-cr, qepA, and oqxAB. Some of these mutations cause only subtle increases in the MIC, i.e., MICs ranging from 0.12 to 0.25 mg/liter for ciprofloxacin (just above the wild-type MIC of ≤0.06 mg/liter). These isolates are difficult to detect with standard ciprofloxacin disk diffusion, and plasmid-mediated resistance, such as qnr, is often not detected by the nalidixic acid screen test. We evaluated 16 quinolone/fluoroquinolone disks for their ability to detect low-level-resistant Salmonella enterica isolates that are not serotype Typhi. A total of 153 Salmonella isolates characterized for the presence (n = 104) or absence (n = 49) of gyrA and/or parC topoisomerase mutations, qnrA, qnrB, qnrD, qnrS, aac(6′)-Ib-cr, or qepA genes were investigated. All isolates were MIC tested by broth microdilution against ciprofloxacin, levofloxacin, and ofloxacin and by disk diffusion using EUCAST or CLSI methodology. MIC determination correctly categorized all isolates as either wild-type isolates (MIC of ≤0.06 mg/liter and absence of resistance genes) or non-wild-type isolates (MIC of >0.06 mg/liter and presence of a resistance gene). Disk diffusion using these antibiotics and nalidixic acid failed to detect some low-level-resistant isolates, whereas the 5-μg pefloxacin disk correctly identified all resistant isolates. However, pefloxacin will not detect isolates having aac(6′)-Ib-cr as the only resistance determinant. The pefloxacin disk assay was approved and implemented by EUCAST (in 2014) and CLSI (in 2015).

Structure based in silico analysis of quinolone resistance in clinical isolates of Salmonella Typhi from India.

Abstract: Enteric fever is a major cause of morbidity in several parts of the Indian subcontinent. The treatment for typhoid fever majorly includes the fluoroquinolone group of antibiotics. Excessive and indiscriminate use of these antibiotics has led to development of acquired resistance in the causative organism Salmonella Typhi. The resistance towards fluoroquinolones is associated with mutations in the target gene of DNA Gyrase. We have estimated the Minimum Inhibitory Concentration (MIC) of commonly used fluoroquinolone representatives from three generations, ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin, for 100 clinical isolates of Salmonella Typhi from patients in the Indian subcontinent. The MICs have been found to be in the range of 0.032 to 8 μg/ml. The gene encoding DNA Gyrase was subsequently sequenced and point mutations were observed in DNA Gyrase in the quinolone resistance determining region comprising Ser83Phe/Tyr and Asp87Tyr/Gly. The binding ability of these four fluoroquinolones in the quinolone binding pocket of wild type as well as mutant DNA Gyrase was computationally analyzed by molecular docking to assess their differential binding behaviour. This study has revealed that mutations in DNA Gyrase alter the characteristics of the binding pocket resulting in the loss of crucial molecular interactions and consequently decrease the binding affinity of fluoroquinolones with the target protein. The present study assists in understanding the underlying molecular and structural mechanism for decreased fluoroquinolone susceptibility in clinical isolates as a consequence of mutations in DNA Gyrase.

Emergence of the first levofloxacin-resistant strains of Streptococcus agalactiae isolated in Italy

Abstract: Of 901 group B streptococcus strains analyzed, 13 (1.4%) were resistant to levofloxacin (MICs of >32 μg/ml for seven isolates, 2 μg/ml for four isolates, and 1.5 μg/ml for four isolates). Mutations in the quinolone resistance-determining regions (QRDRs) of gyrase and topoisomerase IV were identified. A double mutation involving the Ser-81 change to Leu for gyrA and the Ser-79 change to Phe or to Tyr for parC was linked to a high level of fluoroquinolone resistance. In addition, two other mutational positions in parC were observed, resulting in an Asp-83-to-Tyr substitution and an Asp-83-to-Asn substitution. Different mutations were also observed in gyrB, with unknown significance. Most levofloxacin-resistant GBS strains were of serotype Ib and belonged to sequence type 19 (ST19) and clonal complex 19 (CC-19). Most of them exhibited the epsilon gene.

Activity of quinolone CP-115,955 against bacterial and human type II topoisomerases is mediated by different interactions.

Abstract: CP-115,955 is a quinolone with a 4-hydroxyphenyl at C7 that displays high activity against both bacterial and human type II topoisomerases. To determine the basis for quinolone cross-reactivity between bacterial and human enzymes, the activity of CP-115,955 and a series of related quinolones and quinazolinediones against Bacillus anthracis topoisomerase IV and human topoisomerase IIα was analyzed. Results indicate that the activity of CP-115,955 against the bacterial and human enzymes is mediated by different interactions. On the basis of the decreased activity of quinazolinediones against wild-type and resistant mutant topoisomerase IV and the low activity of quinolones against resistant mutant enzymes, it appears that the primary interaction of CP-115,955 with the bacterial system is mediated through the C3/C4 keto acid and the water-metal ion bridge. In contrast, the drug interacts with the human enzyme primarily through the C7 4-hydroxyphenyl ring and has no requirement for a substituent at C8 in order to attain high activity. Despite the fact that the human type II enzyme is unable to utilize the water-metal ion bridge, quinolones in the CP-115,955 series display higher activity against topoisomerase IIα in vitro and in cultured human cells than the corresponding quinazolinediones. Thus, quinolones may be a viable platform for the development of novel drugs with anticancer potential.

Protective effect of Qnr on agents other than quinolones that target DNA gyrase.

Abstract: Qnr is a plasmid-encoded and chromosomally determined protein that protects DNA gyrase and topoisomerase IV from inhibition by quinolones. Despite its prevalence worldwide and existence prior to the discovery of quinolones, its native function is not known. Other synthetic compounds and natural products also target bacterial topoisomerases. A number were studied as molecular probes to gain insight into how Qnr acts. Qnr blocked inhibition by synthetic compounds with somewhat quinolone-like structure that target the GyrA subunit, such as the 2-pyridone ABT-719, the quinazoline-2,4-dione PD 0305970, and the spiropyrimidinetrione pyrazinyl-alkynyl-tetrahydroquinoline (PAT), indicating that Qnr is not strictly quinolone specific, but Qnr did not protect against GyrA-targeting simocyclinone D8 despite evidence that both simocyclinone D8 and Qnr affect DNA binding to gyrase. Qnr did not affect the activity of tricyclic pyrimidoindole or pyrazolopyridones, synthetic inhibitors of the GyrB subunit, or nonsynthetic GyrB inhibitors, such as coumermycin A1, novobiocin, gyramide A, or microcin B17.Thus, in this set of compounds the protective activity of Qnr was confined to those that, like quinolones, trap gyrase on DNA in cleaved complexes.

Frequent topoisomerase IV mutations associated with fluoroquinolone resistance in Ureaplasma species.

Abstract: This study aimed to investigate the role of quinolone resistance-determining regions (QRDRs) of DNA gyrase (encoded by gyrA and gyrB) and topoisomerase IV (encoded by parC and parE) associated with fluoroquinolone resistance. A total of 114 Ureaplasma spp. strains, isolated from clinical female patients with symptomatic infection, were tested for species distribution and susceptibility to four fluoroquinolones. Moreover, we analysed the QRDRs and compared these with 14 ATCC reference strains of Ureaplasma spp. serovars to identify mutations that caused antimicrobial resistance. Our study indicated that moxifloxacin was the most effective fluoroquinolone against Ureaplasma spp. (MIC range: 0.125–32 μg ml− 1). However, extremely high MICs were estimated for ciprofloxacin (MIC range: 1–256 μg ml− 1) and ofloxacin (MIC range: 0.5–128 μg ml− 1), followed by levofloxacin (MIC range: 0.5–64 μg ml− 1). Seven amino acid substitutions were discovered in GyrB, ParC and ParE, but not in GyrA. Ser-83 → Leu/Trp (C248T/G) in ParC and Arg-448 → Lys (G1343A) in ParE, which were potentially responsible for fluoroquinolone resistance, were observed in 89 (77.2 %) and three (2.6 %) strains, respectively. Pro-462 → Ser (C1384T), Asn-481 → Ser (A1442G) and Ala-493 → Val (C1478T) in GyrB and Met-105 → Ile (G315T) in ParC seemed to be neutral polymorphisms, and were observed and occurred along with the amino acid change of Ser-83 → Leu (C248T) in ParC. Interestingly, two novel mutations of ParC and ParE were independently found in four strains. These observations suggest that amino acid mutation in topoisomerase IV appears to be the leading cause of fluoroquinolone resistance, especially the mutation of Ser-83 → Leu (C248T) in ParC. Moxifloxacin had the best activity against strains with Ser-83 → Leu mutation.

Carriage of Class 1 and 2 Integrons in Quinolone, Extended-Spectrum-β-Lactamase-Producing and Multi Drug Resistant E.coli and K.pneumoniae: High Burden of Antibiotic Resistance.

Abstract: Purpose: The study aimed at assessing any association between quinolone resistance, MDR and ESBL production and their relation with the presence of integrons in Esherichia coli and Klebsiella pneumoniae. Methods: E.coli and K.pneumoniae isolated from various clinical infections were fully identified and analyzed for being quinolone resistant. These isolates were further tested for ESBL production, multi drug resistance and carriage of integrons. Results: In total, 135 isolates were confirmed as quinolone resistant. K.pneumoniae was observed as potent ESBL producer in comparison to E.coli. Ciprofloxacin resistance in both organisms was related significantly with the presence of integron class 1, co-presence of class 1 and 2 as well as to the presence of ESBL production (p< 0.001). However, nalidixic acid resistance was related significantly (p< 0.01) with only integron class 1 and to the presence of ESBL production. Class 1 and 2 integrons were found in 73.5% of MDR isolates with 13.2% of them possessing both intI1 and intI2 genes. Conclusion: Prevalence of quinolone resistance together with ESBL production and MDR in E.coli and K.pneumoniae has contributed to the emergence of antibacterial resistance burden. The higher integron prevalence in our isolates advocates the potentiality of these isolates as a source for dissemination of resistance determinants.

Comparative Analysis of Quinolone Resistance in Clinical Isolates of Klebsiella pneumoniae and Escherichia coli from Chinese Children and Adults

Abstract: The objective of this study was to compare quinolone resistance and gyrA mutations in clinical isolates of Klebsiella pneumoniae and Escherichia coli from Chinese adults who used quinolone in the preceding month and children without any known history of quinolone administration. The antimicrobial susceptibilities of 61 isolates from children and 79 isolates from adults were determined. The mutations in the quinolone resistance-determining regions in gyrA gene were detected by PCR and DNA sequencing. Fluoroquinolone resistance and types of gyrA mutations in isolates from children and adults were compared and statistically analyzed. No significant differences were detected in the resistance rates of ciprofloxacin and levofloxacin between children and adults among isolates of the two species (all P > 0.05). The double mutation Ser83→Leu + Asp87→Asn in the ciprofloxacin-resistant isolates occurred in 73.7% isolates from the children and 67.9% from the adults, respectively (P = 0.5444). Children with no known history of quinolone administration were found to carry fluoroquinolone-resistant Enterobacteriaceae isolates. The occurrence of ciprofloxacin resistance and the major types of gyrA mutations in the isolates from the children were similar to those from adults. The results indicate that precautions should be taken on environmental issues resulting from widespread transmission of quinolone resistance.

Characterization of Salmonella Typhimurium DNA gyrase as a target of quinolones.

Abstract: Quinolones exhibit good antibacterial activity against Salmonella spp. isolates and are often the choice of treatment for life-threatening salmonellosis due to multi-drug resistant strains. To assess the properties of quinolones, we performed an in vitro assay to study the antibacterial activities of quinolones against recombinant DNA gyrase. We expressed the S. Typhimurium DNA gyrase A (GyrA) and B (GyrB) subunits in Escherichia coli. GyrA and GyrB were obtained at high purity (>95%) by nickel-nitrilotriacetic acid agarose resin column chromatography as His-tagged 97-kDa and 89-kDa proteins, respectively. Both subunits were shown to reconstitute an ATP-dependent DNA supercoiling activity. Drug concentrations that suppressed DNA supercoiling by 50% (IC50s) or generated DNA cleavage by 25% (CC25s) demonstrated that quinolones highly active against S. Typhimurium DNA gyrase share a fluorine atom at C-6. The relationships between the minimum inhibitory concentrations (MICs), IC50s and CC25s were assessed by estimating a linear regression between two components. MICs measured against S. Typhimurium NBRC 13245 correlated better with IC50s (R = 0.9988) than CC25s (R = 0.9685). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test to identify quinolones with promising activity against S. Typhimurium. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and N-1 cyclopropyl substituents are desirable structural features in targeting S. Typhimurium gyrase. Copyright © 2014 John Wiley & Sons, Ltd.

Antibacterial resistance pattern among Escherichia coli strains isolated from Mansoura hospitals in Egypt with a special reference to quinolones

Abstract: Extensive use of fluoroquinolone antibacterial in clinical practice has been associated with increasing frequency of quinolone-resistant Escherichia coli strains. In the current study, a total of 80 E. coli clinical isolates from Mansoura hospitals patients in Egypt were studied for antibacterial susceptibility pattern against 15 different antibacterials. These strains were tested for quinolones resistance by minimum inhibitory concentration (MIC) determination using broth micro-dilution method. The resistance rate of ciprofloxacin and levofloxacin for E. coli isolates was found to be 60%. PCR was performed for detection of plasmid-mediated quinolone resistance genes including qnrA, qnrB and qnrS. 30 and 61.3% of E. coli isolates were positive for qnrA and qnrB, respectively, whereas qnrS was identified in only 15% of isolates. Quinolone resistance-determining region (QRDR) of gyrA and ParC genes was characterized for 17 ciprofloxacin and levofloxacin resistant E. coli isolates (MIC 12.5-200 µg mL-1). Two mutation sites in gyrA were detected in 17 tested E. coli isolates. However, two mutation sites in parC were detected in four E. coli isolates. The amino acid change at Ser-83 and aspartic-87 in GyrA were the most common mutation sites identified in the isolates. These results indicated that multiple mechanisms of quinolone-resistance are commonly found in E. coli isolated from Mansoura hospitals. Key words: Quinolone resistance, gyrA, parC, qnr gene.

Antimicrobial Susceptibility and SOS-Dependent Increase in Mutation Frequency Are Impacted by Escherichia coli Topoisomerase I C-Terminal Point Mutation

Abstract: Topoisomerase functions are required in all organisms for many vital cellular processes, including transcription elongation. The C terminus domains (CTD) of Escherichia coli topoisomerase I interact directly with RNA polymerase to remove transcription-driven negative supercoiling behind the RNA polymerase complex. This interaction prevents inhibition of transcription elongation from hypernegative supercoiling and R-loop accumulation. The physiological function of bacterial topoisomerase I in transcription is especially important for a rapid network response to an antibiotic challenge. In this study, Escherichia coli with a topA66 single nucleotide deletion mutation, which results in a frameshift in the TopA CTD, was shown to exhibit increased sensitivity to trimethoprim and quinolone antimicrobials. The topoisomerase I-RNA polymerase interaction and the SOS response to the antimicrobial agents were found to be significantly reduced by this topA66 mutation. Consequently, the mutation frequency measured by rifampin selection following SOS induction was diminished in the topA66 mutant. The increased antibiotic sensitivity for the topA66 mutant can be reversed by the expression of recombinant E. coli topoisomerase I but not by the expression of recombinant Mycobacterium tuberculosis topoisomerase I that has a nonhomologous CTD even though the recombinant M. tuberculosis topoisomerase I can restore most of the plasmid DNA linking number deficiency caused by the topA66 mutation. Direct interactions of E. coli topoisomerase I as part of transcription complexes are likely to be required for the rapid network response to an antibiotic challenge. Inhibitors of bacterial topoisomerase I functions and interactions may sensitize pathogens to antibiotic treatment and limit the mutagenic response.

Role of quinolones and quinoxaline derivatives in the advancement of treatment of tuberculosis

Abstract: The need of new chemotherapeutic drugs to improve tuberculosis control and treatment particularly against multidrug-resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium. The atitubercular drugs are used in current chemotherapy have different chemical moieties. In this review, we provide an overview of the quinolone drugs as an antitubercular drug. Generally quinolone drugs are mainly used against many gram-positive and gram-negative bacterial infections including resistance strains also. Various quinolones are being used to control and treatment of tubercular infections including MDR, XDR and atypical Mycobacterium strains. Fluoroquinolones are an important quinolones, especially for strains that are resistant to first-line agents.

Identification of a novel mutation at the primary dimer interface of GyrA conferring fluoroquinolone resistance in Clostridium difficile.

Abstract: The aim of this study was to determine whether alternative resistance mechanisms, other than mutation in the quinolone resistance-determining region (QRDR) of DNA gyrase, could confer fluoroquinolone resistance in Clostridium difficile. An in vitro-generated C. difficile mutant exhibiting increased fluoroquinolone resistance was isolated through antibiotic selection on ciprofloxacin. The QRDR of this mutant was investigated by chain-termination sequencing and was found to be devoid of mutation. To determine the nature of the non-QRDR resistance mechanism in this strain, the genomes of the mutant and wild-type strains were sequenced. The gyrBA region from a collection of clinical isolates exhibiting variable fluoroquinolone resistance levels was also sequenced and was compared with that present in 918 publicly available C. difficile genomic data sets. Whole-genome sequence analysis of the fluoroquinolone-resistant mutant revealed a single non-synonymous substitution (Ala384Asp) at the predicted primary dimer interface of GyrA, far beyond the classically defined QRDR. This novel mutation caused increased resistance to ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin while conferring hypersusceptibility to novobiocin. Several novel extra-QRDR polymorphisms in C. difficile DNA gyrase were identified among clinical isolates, whilst observed fluoroquinolone resistance in strains devoid of gyrBA mutations confirmed the existence of DNA gyrase-independent resistance mechanisms in this species. In conclusion, we report the first non-QRDR mutation to confer fluoroquinolone resistance in C. difficile. Although the Ala384Asp substitution was not detected in clinical isolates, this study revealed a diversity of alternative extra-QRDR polymorphisms in DNA gyrase whose association with fluoroquinolone resistance warrants further investigation.

Quinolones. Nowadays perspectives and mechanisms of resistance

Abstract: Quinolones are a family of synthetic broad-spectrum antimicrobial drugs whose target is the synthesis of DNA. They directly inhibit DNA replication by interacting with two enzymes; DNA gyrase and topoisomerase IV. They have been widely used for the treatment of several community and hospital acquired infections, in the food processing industry and in the agricultural field, making the increasing incidence of quinolone resistance a frequent problem associated with constant exposition to diverse microorganisms. Resistance may be achieved by three non-exclusive mechanisms; through chromosomic mutations in the Quinolone Resistance-Determining Regions of DNA gyrase and topoisomerase IV, by reducing the intracytoplasmic concentrations of quinolones actively or passively and by Plasmid-Mediated Quinolones-Resistance genes, [Qnr determinant genes of resistance to quinolones, variant gene of the aminoglycoside acetyltransferase (AAC(6')-Ib-c)] and encoding genes of efflux pumps (qepA and oqxAB)]. The future of quinolones is uncertain, however, meanwhile they continue to be used in an irrational way, increasing resistance to quinolones should remain as an area of primary priority for research.

C1–C2-linker substituted 1,5-naphthyridine analogues of oxabicyclooctane-linked NBTIs as broad-spectrum antibacterial agents (part 7)

Abstract: Novel bacterial topoisomerase inhibitors (NBTIs) are a recent class of broad-spectrum antibacterial agents targeting bacterial DNA gyrase and topoisomerase IV at a site distinct from quinolone binding. They are not cross-resistant to known antibiotics and present an excellent opportunity to combat drug-resistant bacteria. We have recently reported a series of oxabicyclooctane-linked inhibitors describing the structure–activity relationship around left-hand-side and right-hand-side moieties. In this report, SAR of the benzylic (C-1) and homobenzylic (C-2) positions of the linker moiety has been described. Single and double substitutions by polar and charged (OH, NH2, CO2H) and non-polar (F, Me) groups indicated that a hydroxy substitution at the benzylic or homobenzylic position is preferred for the potency and spectrum. The C-1,2-dihydroxy group was not effective. Amino substitution at C-2 provides a marginal advantage to the Gram-negative activity. It appears that the α-hydroxy enantiomer was preferred. Despite the beneficial effects of C-1 hydroxy–C-1 alkyl substitution in the tricyclics (particularly for attenuation of hERG), methyl tert-carbinols either at C-1 or C-2 had a detrimental effect on the activity without having much effect on the hERG signal. Mono-hydroxy compounds at C-1 and C-2 showed improved intravenous (ED50 2–4 mg kg−1) and oral (ED50 2–5 mg kg−1) efficacy in a mouse model of bacteremia of S. aureus infection.

Novel N-2-(Furyl)-2-(chlorobenzyloxyimino) ethyl Piperazinyl Quinolones: Synthesis, Cytotoxic Evaluation and Structure-activity Relationship

Abstract: Quinolone antibacterials are one of the most important classes of pharmacological agents known as potent inhibitors of bacterial DNA gyrase and topoisomerase IV that efficiently inhibit DNA replication and transcription by generating several double-stranded DNA break. Some quinolone derivatives demonstrated inhibitory potential against eukaryote topoismarase II and substantial dose-dependent cytotoxic potential against some cancerous cells. In present study, synthesis and cytotoxic activity evaluation of new series of N-pipearzinyl quinolones containing N-2-(furyl-2 or 3-yl)-2-(chlorobenzyloxyimino) ethyl moiety 7a-i have been studied. Reaction of quinolone, with 2-bromo-1-(furan-2 or 3-yl)ethanone-O-substituted chlorobenzyloxime in DMF in presence of NaHCO3 at room temperature, gave the title compounds N-2-(furan-2 or 3-yl)-2-(chlorobenzyloxyiminoethyl) quinolone 7a-i. Synthesized compounds were further evaluated in-vitro against three human breast tumor cell lines. Preliminary screening indicated that compound 7 g demonstrated significant growth inhibitory potential against all evaluated cell lines. The results of structure-activity relationship study exhibited that quinolone derivatives are superior in cytotoxic potential compared to 1, 8-naphthyridone series. Furthermore, ethyl quinolone derivatives were more potent cytotoxic agents comparing with cyclopropyl quinolones.