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A series of spiro β-Lactams (4 a-c, 7 a-c) and thiazolidinones (5 a-c, 8 a-c) possessing 1,8-naphthyridine moiety were synthesized in this study. The structure of the newly synthesized compounds has been confirmed by IR, 1 H-NMR, 13 C NMR, mass spectra, and elemental analysis. The synthesized compounds were tested in vitro for their antibacterial and antifungal activity against various strains. The antimicrobial data showed that most of the compounds displayed good efficacy against both bacteria and fungi. The structure-activity relationship (SAR) studies suggested that the presence of electron-withdrawing chloro (3 b, 4 b, and 5 b) and nitro groups (7 b, 8 b) at the para position of the phenyl ring improved the antimicrobial activity of the compounds. The free radical scavenging assay showed that all the synthesized compounds exhibited significant antioxidant activity on DPPH. Compounds 8 b (IC 50 =17.68±0.76 μg/mL) and 4 c (IC 50 =18.53±0.52 μg/mL) showed the highest antioxidant activity compared to ascorbic acid (IC 50 =15.16±0.43 μg/mL). Molecular docking studies were also conducted to support the antimicrobial and SAR results., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Novel bacterial topoisomerase inhibitors (NBTIs) are an important new class of antibacterials targeting bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Notwithstanding their potent antibacterial activity, they suffer from a detrimental class-related hERG blockage. In this study, we designed and synthesized an optimized library of NBTIs comprising different linker moieties that exhibit reduced hERG inhibition and retain inhibitory potencies on DNA gyrase and topoisomerase IV of Staphylococcus aureus and Escherichia coli, respectively, as well as potent antibacterial activities. Substitution of the linker's tertiary amine with polar groups outcome in diminished hERG inhibition. Compound 17 expresses nanomolar enzyme inhibitory potency and antibacterial activity against both Gram-positive and Gram-negative bacteria as well as reduced hERG inhibition relative to our previously published NBTI analogs. Here, we point to some important NBTI's structural features that influence their hERG inhibitory activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Gyrase and topoisomerase IV are the targets of fluoroquinolone antibacterials. However, the rise in antimicrobial resistance has undermined the clinical use of this important drug class. Therefore, it is critical to identify new agents that maintain activity against fluoroquinolone-resistant strains. One approach is to develop non-fluoroquinolone drugs that also target gyrase and topoisomerase IV but interact differently with the enzymes. This has led to the development of the "novel bacterial topoisomerase inhibitor" (NBTI) class of antibacterials. Despite the clinical potential of NBTIs, there is a relative paucity of data describing their mechanism of action against bacterial type II topoisomerases. Consequently, we characterized the activity of GSK126, a naphthyridone/aminopiperidine-based NBTI, against a variety of Gram-positive and Gram-negative bacterial type II topoisomerases, including gyrase from Mycobacterium tuberculosis and gyrase and topoisomerase IV from Bacillus anthracis and Escherichia coli . GSK126 enhanced single-stranded DNA cleavage and suppressed double-stranded cleavage mediated by these enzymes. It was also a potent inhibitor of gyrase-catalyzed DNA supercoiling and topoisomerase IV-catalyzed decatenation. Thus, GSK126 displays a similar bimodal mechanism of action across a variety of species. In contrast, GSK126 displayed a variable ability to overcome fluoroquinolone resistance mutations across these same species. Our results suggest that NBTIs elicit their antibacterial effects by two different mechanisms: inhibition of gyrase/topoisomerase IV catalytic activity or enhancement of enzyme-mediated DNA cleavage. Furthermore, the relative importance of these two mechanisms appears to differ from species to species. Therefore, we propose that the mechanistic basis for the antibacterial properties of NBTIs is bimodal in nature.

Four series of triazolylnaphthyridinone derivatives were synthesized as structural surrogates of nalidixic acid. The targeted derivatives involve: 3-(5-acylamino-2H-1,2,4-triazol-3-yl)-naphtyridin-4-ones 6(a-e); 3-(5-benzylidineamino-2H-1,2,4-triazol-3-yl)-naphthyridin-4-ones 8(a-g) and their 6-bromonaphthyridin-4-one analogs 7(a-e); 9(a-g). The synthesized compounds were evaluated In vitro for their antimicrobial activity against selected resistant strains of G+ve, G-ve, and Mycobacterium phlei. The results revealed remarkable selectivity, of the tested compounds, against Bacillus subtilis and Aggregatibacter actinomycetemcomitans, which are resistant to nalidixic acid. The growth inhibition zones were ranging from 20 to 40 mm at 10 mg/ml and the respective MIC-values ∼3.68-6.3 µM. The results illustrate that the 6-bromo derivatives 7(a-e) and 9(a-g) were more potent than the non-brominated counterparts 6(a-e) and 8(a-e) respectively. Inhibition of E. coli DNA-gyrase supercoiling activity is also evaluated. The 5-(4-methoxybanzamido)-triazolyl-6-bromonaphthyridinone (7e) exhibits IC 50  = 1.94 μg/ml, which is comparable to that of nalidixic acid (IC 50 : 1.74 μg/ml). In addition, the most prominent IC 50 -values are displayed by: (7a;IC 50 : 2.77 μg/ml); (8g; IC 50 : 3.78 μg/ml); and (9d;IC 50 : 3.21 μg/ml). Molecular docking to the active site of DNA-gyrase cleavage complex of Acinetobacter baumannii (PDB code: 2xkk) co-crystallized with moxifloxacin revealed similar binding modes in addition to new interactions. Assessment of drug-likeness characteristics illustrate that the synthesized compounds showed agreement to Lipinski's and Veper's parameters. The study could offer an exceptional framework that may lead to the discovery of new potent antimicrobial agents., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The bacterial ribosomal decoding region of the aminoacyl-tRNA site (A-site) is one of the most validated target RNAs for antibiotic agents. Although natural aminoglycosides are well-characterized A-site binding ligands, high off-target effects and the growing emergence of bacterial resistance against aminoglycosides limit their clinical use. To circumvent these concerns with the aminoglycoside family, non-aminoglycoside A-site binding ligands have great potential as novel antibiotics against bacterial infections. This work describes a new class of small heterocyclic ligands based on the 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) structure for the bacterial (Escherichia coli) A-site. ATMND possessing an aminoethyl side chain is found to strongly and selectively bind to the internal loop of the A-site (K d =0.44 μm; pH 7.0, I=0.06 m, 5 °C). Significantly, this ligand shows the tightest binding reported to date among non-aminoglycoside ligands. The binding study based on the thermodynamics and molecular modelling reveals key molecular interactions of ATMND-C 2 -NH 2 for high affinity to the A-site. This ligand is also demonstrated to be applicable to the fluorescence indicator displacement assay for assessing ligand/A-site interactions., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Three novel mixed ligand metal complexes have been synthesized by the reaction of Zn(II), Sn(II), and Ce(III) with gemifloxacin (GMFX) in the presence of glycine (Gly) (1:1:1 molar ratio). The coordination possibility of the two ligands toward metal ions has been proposed in the light of elemental analysis, molar conductance, spectral infrared (IR), ultraviolet-visible (UV-Vis) and proton-nuclear magnetic resonance (¹H NMR), and magnetic studies. Results suggest that GMFX and Gly interact with the metal ions as bidentate ligands. Electronic and magnetic data proposed the octahedral structure for all complexes under investigation. Antibacterial screening of the compounds was carried out in vitro against two Gram-positive bacteria, Clavibacter michiganensis and Bacillus megaterium , and two Gram-negative bacteria, Escherichia coli and Xanthomonas campestris . Antifungal activity was performed in vitro against Rhizoctonia solani , Sclerotinia sclerotiorum , Aspergillus niger , Botrytis cinerea , and Penicillium digitatum . The ligands and their complexes were also screened for their antioxidant activity. Results showed that some metal complexes showed more biological efficiency than the parent GMFX drug., Competing Interests: The authors declare no conflicts of interest.

During the construction of bioactive molecules, regioselective alkylation of heterocyclic, N/O ambident nucleophiles is a frequently encountered synthetic transformation. In this framework, specific attention is required to unambiguously determine the structures of obtained reaction products. As part of our project on quinoloxyacetamide based antimycobacterial agents, a series of N- or O- alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives were prepared during the course of which we observed unexpected selectivity issues. After finding that no consistent procedure existed in the literature for assigning regioisomers of this type, we applied three readily accessible NMR experiment types ( 13 C NMR, HSQC/HMBC and NOE) to resolve any uncertainties regarding the obtained regioisomeric structures. Furthermore, the antimycobacterial activity of all final compounds was evaluated with the best compound 23 showing potent antitubercular activity (MIC = 1.25 μM) without cytotoxic effects., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The compound N-(2-hydroxybenzylidene)-1-ethyl-1, 4-dihydro-7-methyl-4-oxo-1, 8 naphthyridine-3-carbohydrazide (LH) and its Cu (II), Co (II) and Zn (II) complexes were synthesized and characterized. The absorption spectral titrations and competitive DNA binding studies depicted those complexes of title compound bind to CT-DNA through intercalation. Interestingly [Cu (II)-(L2)] showed relatively high binding constant value (6.61 x 10(5) M(-1)) compared to [Co (II)-(L2)] (4.378× 10(5) M(-1)) and [Zn (II)-(L2)] (3.1x10(5) M(-1)). Ligand and its complexes were also examined for DNA nuclease activity against pBR-322 plasmid DNA, which showed that [Cu (II)-(L2)] had the best hydrolytic cleavage property displaying prominent double-strand DNA cleavage. In addition, antioxidant activities of the ligand and its metal complexes investigated through scavenging effects for DPPH radical in- vitro, indicated their potentiality as good antioxidants. The in vitro anti-bacterial study inferred the better anti-bacterial activity of [Cu (II)-(L2)] and this was also correlated theoretically by employing docking studies wherein [Cu (II)-(L2)] displayed good Gold score and Chem score. Finally the in vitro anti- proliferative activity of studied compounds was tested against HeLa and MCF-7 cell lines. Interestingly [Cu (II)-(L2)] displayed lower IC50 value and lower percentage of viability in both HeLa and MCF-7 cell lines.

Oxabicyclooctane linked novel bacterial topoisomerase inhibitors (NBTIs) are new class of recently reported broad-spectrum antibacterial agents. They target bacterial DNA gyrase and topoisomerase IV and bind to a site different than quinolones. They show no cross-resistance to known antibiotics and provide opportunity to combat drug-resistant bacteria. A structure activity relationship of the C-2 substituted ether analogs of 1,5-naphthyridine oxabicyclooctane-linked NBTIs are described. Synthesis and antibacterial activities of a total of 63 analogs have been summarized representing alkyl, cyclo alkyl, fluoro alkyl, hydroxy alkyl, amino alkyl, and carboxyl alkyl ethers. All compounds were tested against three key strains each of Gram-positive and Gram-negative bacteria as well as for hERG binding activities. Many key compounds were also tested for the functional hERG activity. Six compounds were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection. Significant tolerance for the ether substitution (including polar groups such as amino and carboxyl) at C-2 was observed for S. aureus activity however the same was not true for Enterococcus faecium and Gram-negative strains. Reduced clogD generally showed reduced hERG activity and improved in vivo efficacy but was generally associated with decreased overall potency. One of the best compounds was hydroxy propyl ether (16), which mainly retained the potency, spectrum and in vivo efficacy of AM8085 associated with the decreased hERG activity and improved physical property., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 μM) profile., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. (R)-Hydroxy-1,5-naphthyridinone left-hand side (LHS) oxabicyclooctane linked pyridoxazinone right-hand side (RHS) containing NBTIs showed a potent Gram-positive antibacterial profile. SAR around the RHS moiety, including substitutions around pyridooxazinone, pyridodioxane, and phenyl propenoids has been described. A fluoro substituted pyridoxazinone showed an MIC against Staphylococcus aureus of 0.5 μg/mL with reduced functional hERG activity (IC50 333 μM) and good in vivo efficacy [ED90 12 mg/kg, intravenous (iv) and 15 mg/kg, oral (p.o.)]. A pyridodioxane-containing NBTI showed a S. aureus MIC of 0.5 μg/mL, significantly improved hERG IC50 764 μM and strong efficacy of 11 mg/kg (iv) and 5 mg/kg (p.o.). A phenyl propenoid series of compounds showed potent antibacterial activity, but also showed potent hERG binding activity. Many of the compounds in the hydroxy-tricyclic series showed strong activity against Acinetobacter baumannii, but reduced activity against Escherichia coli and Pseudomonas aeruginosa. Bicyclic heterocycles appeared to be the best RHS moiety for the hydroxy-tricyclic oxabicyclooctane linked NBTIs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a (R)-hydroxy-1,5-naphthyridinone moiety (7) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED50) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170 μM). In general, lower logD attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1,5-naphthyridinone based oxabicyclooctane linked NBTIs are described., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Gemifloxacin mesylate (GFM) is a synthetic, broad-spectrum, fluoroquinolone antibacterial agent. It is different from other class members because it achieves adequate plasma concentrations to inhibit both topoisomerase IV and gyrase. The aim of this study was to develop and validate a dissolution test for GFM in coated tablets, using a simulated absorption profile based on in vivo data obtained from the literature. The fraction and percentage of the dose absorbed were calculated using model-dependent Loo-Riegelman approach for two compartments. The best in vitro dissolution profile was obtained using 900 mL of pH 6.0 phosphate buffer as a dissolution medium at 37 °C ± 0.5 °C and paddles at 50 rpm. The in vitro dissolution samples were analyzed using a liquid chromatography method, and the validation was performed according to USP 34 (2011). The method showed specificity, precision, accuracy, robustness and linearity. Under these conditions, a level-A in vitro-in vivo correlation was suggested (r = 0.9926). The prediction errors were calculated to determine the validity and accuracy of the suggested correlation. The dissolution test can be used to evaluate the dissolution profile of GFM-coated tablets and minimize the number of bioavailability studies as part of new formulation development.

The synthesis of (-)-1, a potent antibacterial agent, was achieved stereoselectively in nine steps from readily available starting materials. Directed metalations were developed to assemble a pentasubstituted pyridine with appropriately positioned aldehyde and dimethylmorpholine substituents for a key tertiary amino effect reaction (T-reaction) that led to the spirocylic architecture. Ultimately, (-)-1 was isolated as the thermodynamically most favored stereoisomer.

A new aaptamine class alkaloid, designated 2-methoxy-3-oxoaaptamine (1), together with seven known aaptamines (2-8) were isolated from a marine sponge of Aaptos sp. as anti-mycobacterial substances against active and dormant bacilli. The chemical structure of 1 was determined on the basis of spectroscopic analysis. Compound 1 was anti-mycobacterial against Mycobacterium smegmatis in both active growing and dormancy-inducing hypoxic conditions with a minimum inhibitory concentration (MIC) of 6.25 μg/ml, and compounds 2, 5, 6, and 7 showed anti-mycobacterial activities under hypoxic condition selectively, with MIC values of 1.5-6.25 μg/ml.

A simple visible spectrophotometric method was developed for the determination of gemifloxacin mesylate (GFM) in tablets. The method was based on the formation of a yellow ion-pair complex between the basic nitrogen of the drug and the sulfonphthalein acid dye in phthalate buffer. The method was validated by the study of its specificity, linearity, precision, accuracy, and robustness. The assay was compared with an LC and a microbiological method, and the analysis of variance showed no significant difference between the methods (P>0.05). The results demonstrated that the visible spectrophotometric method is suitable for determination of GFM in tablets, even in the presence of a synthetic impurity.

The solid phase FTIR and FT-Raman spectra of 1-ethyl-1,4-dihydro-7-methyl-4oxo-1,8 napthyridine-3-carboxylic acid (EDMONCA) have been recorded in the regions 4000-500 and 4000-400 cm(-1) respectively. The equilibrium geometry, harmonic vibrational frequencies have been investigated by DFT/B3LYP and B3PW91 methods with 6-311G (d,p) basis set. The different between the observed and scaled wave number values of most of the fundamental is very small. The assignments of the vibrational spectra have been carried out with the aid of normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology (SQMFFM). Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. UV-Visible spectrum of the compound was recorded and the electronic properties HOMO and LOMO energies were measured. The electric dipole moment (μD) and first hyperpolarizability (βtot) values of the investigated molecule were computed using ab initio quantum mechanical calculations. The calculated results also show that the EDMONCA molecule may have microscopic nonlinear optics (NLO) behavior with non-zero values. (1)H and (13)C NMR spectra were recorded and (1)H and (13)C nuclear magnetic resonance chemical shift of the molecule were calculated using the gauge independent atomic orbital (GIAO) method. Thermal stability of EDMONCA was studied by thermogravimetric analysis (TGA). Next Fukui function was calculated to explain the chemical selectivity or reactivity site in EDMONCA. Finally molecular electrostatic potential (MEP) and other molecular properties were performed., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Several phenyl substituted naphthalenes and isoquinolines have been identified as antibacterial agents that inhibit FtsZ-Zing formation. In the present study we evaluated the antibacterial of several phenyl substituted quinoxalines, quinazolines and 1,5-naphthyridines against methicillin-sensitive and methicillin-resistant Staphylococcusaureus and vancomycin-sensitive and vancomycin-resistant Enterococcusfaecalis. Some of the more active compounds against S. aureus were evaluated for their effect on FtsZ protein polymerization. Further studies were also performed to assess their relative bactericidal and bacteriostatic activities. The notable differences observed between nonquaternized and quaternized quinoxaline derivatives suggest that differing mechanisms of action are associated with their antibacterial properties., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The oral (po) bioavailability of gemifloxacin mesylate in rats and its possible association with efflux transporters was investigated. The apparent permeabilities (Papp) of gemifloxacin across the Caco-2 cell monolayer were 1.20 ± 0.09 × 10(-5) cm/s for apical to basal (absorptive) transport, and 2.13 ± 0.6 × 10(-5) cm/s for basal to apical (secretory) transport for a 5-500 μM concentration range, suggesting the involvement of a carrier-mediated efflux in the secretory transport. The secretory transport in Caco-2 cells was significantly decreased by MRP2 (MK571) and BCRP (Ko143) inhibitors. The secretory transport was distinct in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells, and the affinity was highest for MRP2, followed by BCRP and P-gp. The efflux was significantly decreased by verapamil and Ko143, but not significantly by MK571. The comparative po bioavailability in rats was increased by the preadministration of Ko143 (four-fold), MK571 (two-fold) and verapamil (two-fold). Efflux transporters appeared to significantly limit the bioavailability of gemifloxacin in rats, suggesting their possible contribution to the low bioavailability of the drug in the human (70%).

A series of novel gemifloxacin (GMFX) derivatives containing a substituted benzyloxime moiety with remarkable improvement in lipophilicity were synthesized. The target compounds evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that most of the target compounds have considerable potency against all of the tested gram-positive strains including MRSA and MRSE (MIC: <0.008-8 μg/mL), although they are generally less active than the references against the gram-negative strains. In particular, compound 11l (MIC: <0.008-4 μg/mL) was found to be 8-2048 and 2-128 times more potent than levofloxacin (LVFX) and GMFX against the gram-positive strains, respectively. Moreover, against MRSA clinical isolates, 11l (MIC(90): 1 μg/mL) is 8-fold more active than GMFX, and 2-fold more active than GMFX and moxifloxacin against MRSE clinical isolates (MIC(90): 4 μg/mL)., (Crown Copyright © 2012. Published by Elsevier Masson SAS. All rights reserved.)

A series of novel naphthyridone derivatives containing mono/difluoro-methyloxime pyrrolidine scaffolds were designed and synthesized. These derivatives were initially evaluated for their in vitro antibacterial activity and compounds 13a1, b1 were chosen for further evaluation their in vivo activity against systemic infections in mice. The results indicate that all of the target compounds have considerable in vitro antibacterial activity. In the in vivo experiments, 13b1 was found to be more effective than the parent drug gemifloxacin against the tested five strains, and especially its activity (ED(50):21.27 mg/kg) is 5.2-6.1 times more potent than gemifloxacin and ciprofloxacin against clinically important Gram-negative pathogen Pseudomonas aeruginosa., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A sensitive electroanalytical method for determination of gemifloxacin in pharmaceutical formulation has been investigated on the basis of the enhanced electrochemical response at multi-walled carbon nanotubes modified glassy carbon electrode in the presence of CTAB. Solubilized system of different surfactants including SDS, Tween-20 and CTAB were taken for the study of electrochemical behaviour of gemifloxacin at modified electrode. The reduction peak current increases in the presence of CTAB while other surfactants show opposite effect. The modified electrode exhibits catalytic activity, high sensitivity, stability and is applicable over wide range of concentration for the determination of gemifloxacin. The mechanism of electrochemical reduction of gemifloxacin has been proposed on the basis of CV, SWV, DPV and coulometeric techniques. The proposed squarewave voltammetric method shows linearity over the concentration range 2.47-15.5 μg/mL. The achieved limits of detection (LOD) and quantification (LOQ) are 0.90 ng/mL and 3.0 ng/mL respectively., (Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.)

The validation of a microbiological assay applying the cylinder-plate method to determine the quinolone gemifloxacin mesylate (GFM) content is described. Using a strain of Staphylococcus epidermidis ATCC 12228 as the test organism, the GFM content in tablets at concentrations ranging from 0.5 to 4.5 μg mL(-1) could be determined. A standard curve was obtained by plotting three values derived from the diameters of the growth inhibition zone. A prospective validation showed that the method developed is linear (r=0.9966), precise (repeatability and intermediate precision), accurate (100.63%), specific and robust. GFM solutions (from the drug product) exposed to direct UVA radiation (352 nm), alkaline hydrolysis, acid hydrolysis, thermal stress, hydrogen peroxide causing oxidation, and a synthetic impurity were used to evaluate the specificity of the bioassay. The bioassay and the previously validated high performance liquid chromatographic (HPLC) method were compared using Student's t test, which indicated that there was no statistically significant difference between these two validated methods. These studies demonstrate the validity of the proposed bioassay, which allows reliable quantification of GFM in tablets and can be used as a useful alternative methodology for GFM analysis in stability studies and routine quality control. The GFM reference standard (RS), photodegraded GFM RS, and synthetic impurity samples were also studied in order to determine the preliminary in vitro cytotoxicity to peripheral blood mononuclear cells. The results indicated that the GFM RS and photodegraded GFM RS were potentially more cytotoxic than the synthetic impurity under the conditions of analysis applied., (Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.)

An efficient enantioselective total synthesis of the potent antibiotic GSK966587 was accomplished. Highlights of the synthesis include two innovative Heck reactions, a highly selective zincate base directed ortho-metalation, Sharpless asymmetric epoxidation, and a fully convergent final step fragment coupling.

A simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to evaluate the accumulation of gemifloxacin in different tissues of Wister albino rat. The analytical method consists of the homogenization of tissues followed by simple liquid-liquid extraction and determination of gemifloxacin by an LC-MS/MS. The analyte was separated on a Peerless basic C(18) column (33 mm x 4.6 mm, 3 microm) with an isocratic mobile phase of methanol-water containing formic acid (1.0%, v/v) (9:1, v/v) at a flow rate of 0.6 ml/min. The MS/MS detection was carried out by monitoring the fragmentation of m/z 390.100-->372.100 for gemifloxacin and m/z 332.100-->314.200 for ciprofloxacin (internal standard; IS) on a triple quadrupole mass spectrometer. The validated method was accurate, precise and rugged with good linearity in all tissue homogenates. The accuracy and precision value obtained from six different sets of quality control samples of all tissues and serum analyzed in separate occasions within 91.833-102.283% and 0.897-5.291%, respectively. The method has been successfully applied to tissue distribution studies of gemifloxacin. The present study demonstrates that the highest tissue concentration of gemifloxacin was obtained in lung (11.891 ng/g), followed by liver (10.110 ng/g), kidney (10.095 ng/g), heart (4.251 ng/g), testis (3.750 ng/g), stomach (3.182 ng/g), adipose tissue (1.116 ng/g) and brain (0.982 ng/ml) in 3h after multiple oral dosing of 200mg gemifloxacin mesylate for 7 days. This method may also be used for gemifloxacin tissue distribution modeling study in rat tissues and antibiotic residue analyses in other animal tissues., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

A series of 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and introduced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, to afford the corresponding fluoroquinolones in 40-83% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. Among them, the quinolone 1-cyclopropyl-6-fluoro-7-(4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (34.15) exhibited comparable antibacterial activity against quinolone-susceptible and multidrug-resistant strains, especially to Staphylococcus aureus and Staphylococcus epidermidis, in comparison with ciprofloxacin and vancomycin., (2010 Elsevier Ltd. All rights reserved.)

A series of 2-substituted 1,2-dihydro-3-phenyl-1-(trichloromethyl)benzo[b][1,6]naphthyridines were synthesized and their in vitro antiproliferative activities were examined against human solid tumor cell lines and relevant strains of bacteria and Candida. The compounds induced considerably growth inhibition in all cancer cell lines, whilst showed inactive against microbial strains. Furthermore, we found analog 2-ethoxy-1H-pyrano[4,3-b]quinoline as selective inhibitor of microbial strains., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Spiropiperidine naphthyridinone inhibitors of Staphylococcus aureus and Escherichia coli FabI have been prepared. Compounds 14a and 14c were identified as having sub-nanomolar E. coli FabI activity and are among the most potent FabI inhibitors yet described. The structural model of 14a bound to E. coli FabI is shown.

A residual silanol group-protecting chiral stationary phase (CSP) based on optically active (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 was successfully applied to the resolution of fluoroquinolone compounds including gemifloxacin mesylate. The chiral recognition ability of the residual silanol group-protecting CSP was generally greater than that of the residual silanol group-containing CSP. From these results, it was concluded that the simple protection of the residual silanol groups of the latter CSP with lipophilic n-octyl groups can improve its chiral recognition ability for the resolution of racemic fluoroquinolone compounds. The chromatographic resolution behaviors were investigated as a function of the content and type of organic and acidic modifiers and the ammonium acetate concentration in aqueous mobile phase and the column temperature. Especially, the addition of ammonium acetate to the mobile phase was found to be a quite effective means of reducing the enantiomer retentions without sacrificing the chiral recognition efficiency of the CSP.

Bacterial DNA gyrase and topoisomerase IV are selective targets of fluoroquinolones. Topoisomerase IV versus gyrase and Gram-positive versus Gram-negative behavior was studied based on the different recognition of DNA sequences by topoisomerase-quinolone complexes. A careful statistical analysis of preferred bases was performed on a large number (>400) of cleavage sites. We found discrete preferred sequences that were similar when using different enzymes (i.e. gyrase and topoisomerase IV) from the same bacterial source, but in part diverse when employing enzymes from different origins (i.e. Escherichia coli and Streptococcus pneumoniae). Subsequent analysis on the wild-type and mutated consensus sequences showed that: (i) Gn/Cn-rich sequences at and around the cleavage site are hot spots for quinolone-mediated strand breaks, especially for E. coli topoisomerases: we elucidated positions required for quinolone and enzyme recognition; (ii) for S. pneumoniae enzymes only, A and T at positions -2 and +6 are discriminating cleavage determinants; (iii) symmetry of the target sequence is a key trait to promote cleavage and (iv) the consensus sequence adopts a heteronomous A/B conformation, which may trigger DNA processing by the enzyme-drug complex.

As part of an investigation to generate optimized drug leads from marine natural pharmacophores for the treatment of neoplastic and infectious diseases, a series of novel isoaaptamine analogs were prepared by coupling acyl halides to the C9 position of isoaaptamine (2) isolated from the Aaptos sponge. This library of new semisynthetic products was evaluated for biological activity against HIV-1, Mtb, AIDS-OI, tropical parasitic diseases, and cancer. Compound 4 showed potent activity against HIV-1 (EC(50) 0.47microg/mL), compound 19 proved to possess remarkable activity against Mycobacterium intracellulare with an IC(50) and MIC value of 0.15 and 0.31microg/mL, while compounds 4 and 17 possessed anti-leishmanial activity with IC(50) values of 0.1 and 0.4microg/mL, respectively. Compounds 16 and 17 showed antimalarial activity with EC(50) values of 230 and 240ng/mL, respectively, and compound 14 exhibited an EC(50) of 0.05microM against the Leukemia cell line K-562.

We describe the synthesis and antibacterial activity of a series of tetracyclic naphthyridones. The members of this series act primarily via inhibition of bacterial translation and belong to the class of novel ribosome inhibitors (NRIs). In this paper we explore the structure-activity relationships (SAR) of these compounds to measure their ability both to inhibit bacterial translation and also to inhibit the growth of bacterial cells in culture. The most active of these compounds inhibit Streptococcus pneumoniae translation at concentrations of <5 microM and have minimum inhibitory concentrations (MICs) of <8 microg/mL against clinically relevant strains of bacteria.

In vitro activities of erythromycin A, telithromycin, and two investigational ketolides, JNJ-17155437 and JNJ-17155528, were evaluated against clinical bacterial strains, including selected common respiratory tract pathogens. Against 46 macrolide-susceptible and -resistant Streptococcus pneumoniae strains, the MIC(90) (MIC at which 90% of the isolates tested were inhibited) of the investigational ketolides was 0.25 microg/ml, twofold lower than that of telithromycin and at least 64-fold lower than that of erythromycin A. Against erm(B)-containing pneumococci, the MIC(90) of all the ketolides was 0.06 microg/ml. The MIC(90) of the investigational ketolides against mef(A)-containing pneumococci or pneumococci with both mef(A) and erm(B) was 0.25 microg/ml, two-and fourfold lower, respectively, than that of telithromycin. In contrast, the MICs of the investigational ketolides against macrolide-resistant S. pneumoniae strains with ribosomal mutations were similar to or, in some cases, as much as eightfold higher than those of telithromycin. Against Haemophilus influenzae, MICs of all the ketolides were < or =2 microg/ml. Against three Moraxella catarrhalis isolates, the MIC of the ketolides was 0.25 microg/ml. The ketolides inhibited in vitro protein synthesis, with 50% inhibitory concentrations ranging from 0.23 to 0.27 microM. In time-kill studies against macrolide-susceptible and erm- or mef-containing pneumococci, the ketolides were bacteriostatic to slowly bactericidal, with 24-h log(10) decreases ranging from 2.0 to 4.1 CFU. Intervals of postantibiotic effects for the ketolides against macrolide-susceptible and -resistant S. pneumoniae were 3.0 to 8.1 h.

Structure-activity relationships for a recently discovered novel ribosome inhibitor (NRI) class of antibacterials were investigated. Preliminary efforts to optimize protein synthesis inhibitory activity of the series through modification of positions 3 and 4 of the naphthyridone lead template resulted in the identification of several biochemically potent analogues. A lack of corresponding whole cell antibacterial activity is thought to be a consequence of poor cellular penetration as evidenced by the enhancement of activity observed for a lead analogue tested in the presence of a cell permeabilizing agent.

DW-286a is a new class of fluoronaphthyridone antibiotic. Its effect on the central nervous system, general behavior, and cardiovascular, respiratory, and other organ systems were studied. The doses given were 30, 50, 100, 150, 300, and 1000 mg/kg and drugs were administered orally. DW-286a did not show any effects on general behavior, motor coordination, analgesic action, seizure and mortality, blood pressure and heart rate, contractile response of isolated guinea pig ileums, and renal function. On the other hand, DW-286a decreased spontaneous locomotor activity from 120 to 240 min after administration at the doses of 300 and 1000 mg/kg and the respiration rate from 30 to 240 min after the administration of doses up to 100 mg/kg. The sleeping time and body temperature were increased significantly in mice at the dose of 1000 mg/kg. DW-286a increased the charcoal transport significantly at doses of 300 and 1000 mg/kg. DW-286a inhibited gastric acid secretion, reduced the volume of the gastric juice and total acidity, and increased the pH dose dependently. Based on the above results, it was concluded that DW-286a affects spontaneous locomotor activity, respiration and body temperature, gastrointestinal transport, gastric secretory action, and hexobarbital sleeping time at high doses.

Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.

A series of 1,8-naphthyridine derivatives variously substituted in the 2, 3, 4 and 7 positions were synthesized for in vitro evaluation of antimycobacterial activity in accordance with an international program with the tuberculosis antimicrobial acquisition and coordinating facility (TAACF). Several compounds 4, 8, 12, 14, 19, 29 and 30, when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H37Rv, showed an interesting activity with % inhibition in the range 38-96%. The most effective substituent in position 2, 4 or 7 of the 1,8-naphthyridine nucleus seem to be the piperidinyl group.

In the present study, a series of 2-substituted-4-methyl-7-amino/4,7-dimethyl-1,8-naphthyridines were synthesized and characterized by IR, 1H-NMR and elemental analysis. The compounds were investigated for anticonvulsant (125, 250 mg/kg), cardiac and antimicrobial activities. The compounds were screened for antibacterial activity against gram (+) bacteria (Staphylococcus epidermidis, Bacillus subtilis, Enterococcusfaecalis and Micrococcus luteus) and gram (-) bacteria (Proteus vulgaris, Pseudomonas aeruginosa, Escherichia coli and Salmonella typhi). All the compounds except 2-(3'-phenylaminopropyloxy)-4-methyl-7-amino-1,8-naphthyridine exhibited significant anticonvulsant activity. The anticonvulsant activity of 2-(3-morpholino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3'-diphenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine and 2-(3'-diethanolamino-propyloxy)-4,7-dimethy-1,8-naphthyridine at the dose of 250 mg/kg were found to be equivalent to diazepam (5 mg/kg). Sympathetic blocking activity was observed with 2-(3'-phenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine, 2-(3'-diethanolamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine and 2-(3'-diphenylamino-2'-hydroxypropyloxy)-4-methyl-7-amino-1,8-naphthyridine only. All the compounds were devoid of antibacterial activity against the tested bacteria.

BMY 45243 is the first representative of 5-amino naphthyridone derivatives prepared following a new methodology developed by the authors. BMY 45243 is a highly lipophilic compound, very active in vitro and in vivo on S. aureus and was found to be as potent as ciprofloxacin on Gram-negative organisms with identical in vivo activity against Pseudomonas aeruginosa. Pharmacokinetics in mice showed better AUC and Cmax and longer t1/2 for BMY 45243 than for sparfloxacin and ciprofloxacin.