Synthesis of various 3-nitropropionamides as Mycobacterium tuberculosis isocitrate lyase inhibitor

Various 3-nitropropionamides were synthesized and evaluated for in vitro activities against log and starved phase culture of two mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among 22 compounds, 1-cyclopropyl-7-(3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (22) was found to be the most active compound in vitro with MICs of 0.16 and 0.04 μM against log- and starved-phase culture of MTB. Compound 22 also showed good enzyme inhibition of MTB ICL with IC(50) of 0.10 ± 0.01 μM. The docking studies also confirmed the binding potential of the compounds at the ICL active site.     

The fungus Pestalotiopsis guepini as a model for biotransformation of ciprofloxacin and norfloxacin

The metabolism of the fluoroquinolone drugs ciprofloxacin and norfloxacin by Pestalotiopsis guepini strain P-8 was investigated. Cultures were grown at 28 degrees C in sucrose/peptone broth for 18 days after dosing with ciprofloxacin (300 microM) or norfloxacin (313 microM). Four major metabolites were produced from each drug; and these were purified by high-performance liquid chromatography and identified by mass spectrometry and proton nuclear magnetic resonance spectroscopy. Ciprofloxacin metabolites included N-acetylciprofloxacin (52.0%), desethylene-N-acetylciprofloxacin (9.2%), N-formylciprofloxacin (4.2%), and 7-amino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.3%). Norfloxacin metabolites included N-acetylnorfloxacin (55.4%), desethylene-N-acetylnorfloxacin (8.8%), N-formylnorfloxacin (3.6%), and 7-amino-1-ethyl-6-fluoro4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.1%). N-Formylciprofloxacin and the four transformation products from norfloxacin are all known to be mammalian metabolites.     

Synthesis of novel quinolone and quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)amides: a late-stage diversification approach to potent 5HT1B antagonists

Multiparallel amenable syntheses of 6-methoxy-8-amino-4-oxo-1,4-dihydroquinoline-2-carboxylic acid-(4-morpholin-4-yl-phenyl)amides (I) and 4-amino-6-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)amides (II) which facilitate late-stage diversification at the 8-position of (I) and at the 4- and 8-positions of (II) are described. The resulting novel series were determined to contain potent 5HT(1B) antagonists. Preliminary SAR data are presented.     

The synthesis and biological evaluation of a novel series of C7 non-basic substituted fluoroquinolones as antibacterial agents

A series of non-basic building blocks was synthesized and introduced to the C7 position of the quinolone nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid to afford the corresponding fluoroquinolones in 46–85% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The sulfur-containing quinolone, 7-(2-thia-5-azabicyclo[2.2.1]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid exhibited a superior antibacterial activity against quinolone-susceptible and multidrug-resistant strains in comparison with the clinically used fluoroquinolones ciprofloxacin and vancomycin, especially to the Streptococcus pneumonia and multidrug-resistant S. pneumonia clinical isolates.     

Synthesis and antibacterial properties of new N4-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids

Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and primary α-amino acids (exemplified by glycine, alanine, and l-valine) in aqueous ethanolic NaHCO(3) at 70-80°C for 24-72?h produced the respective N-(4-oxoquinolin-7-yl)-α-amino acids (6a-c). The latter derivatives underwent reductive lactamization upon treatment with Na(2)S(2)O(4) in aqueous ethanol to afford moderate yields of the corresponding pyrido[2,3-f]quinoxaline-8-carboxylic acids (8a-c). Acetylation of 8a-c using acetyl chloride afforded N(4)-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids (9a-c). The structures, assigned to these new heterocyclic products, are supported by analytical and spectral data. The synthesized compounds (6a-c/9a-c) showed appreciable antibacterial activity as compared with ciprofloxacin.     

4-Substituted 4-(1H-1,2,3-triazol-1-yl)piperidine: Novel C7 moieties of fluoroquinolones as antibacterial agents

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.     

Synthesis of novel ciprofloxacin analogues and evaluation of their anti-proliferative effect on human cancer cell lines

A series of twenty two novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substituted piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues have been synthesized, characterized (¹H NMR, ¹³C NMR and LCMS) and evaluated for their inhibitory activity on the proliferation of human caucasian acute lymphoblastic leukemia cells (CCRF-CEM), breast adenocarcinoma cells (MDA-MB-468) and human colon carcinoma cells (HCT-116). Among all the synthesized ciprofloxacin analogues 3t at 50 μM showed comparable potency to doxorubicin (10 μM) in all three cell lines and 3j inhibited proliferation of MDA-MB-468 up to 35% selectively over other two cell lines.     

Synthesis and antimycobacterial evaluation of newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids

Thirty-four newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids were synthesized from 1,2,3,4-tetrafluoro benzene and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase. Among the synthesized compounds, 7-(1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolin-2(1H)-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylic acid (13n) was found to be the most active compound in vitro with MIC of 0.16 and 0.33 microM against MTB and MDR-TB, respectively. In the in vivo animal model 13n decreased the bacterial load in lung and spleen tissues with 2.54 and 2.92-log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 13n also inhibited the supercoiling activity of mycobacterial DNA gyrase with IC(50) of 30.0 microg/ml.     

Biochemical Characterization,Phytotoxic Effect and Antimicrobial Activity against Some Phytopathogens of New Gemifloxacin Schiff Base Metal Complexes

String of Fe(III), Cu(II), Zn(II) and Zr(IV) complexes were synthesized with tetradentateamino Schiff base ligand derived by condensation of ethylene diamine with gemifloxacin. The novel Schiff base (4E,4′E)-4,4′-(ethane-1,2-diyldiazanylylidene)bis{7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid} (GMFX-en) and its metal complexes were identified and confirmed by elemental analyses, FT-IR, UV/VIS, ¹H-NMR spectra, magnetic susceptibility, conductometric measurements and thermal analyses. The FT-IR spectral data showed the chelation behavior of GMFX-en toward the metal ions through oxygen of carboxylate group and nitrogen of azomethine group. In the light of all spectral data, these complexes presumably have octahedral geometry configurations. Thermal analysis specified that the decaying of the metal complexes exist in two or three steps with the final residue metal oxides. Antimicrobial activity of the new prepared metal complexes was screened against some common phytopathogens and their mode of action has been also discussed. The potential phytotoxic effectiveness of the new complexes was furthermore inspected on two commonly experimental plants. The complexes showed significant antimicrobial and phytotoxic effects against the majority of tested phytopathogens and the two tested plants, respectively. The potential antimicrobial activity of the complexes proved their possibility to be used successfully in agropharmacutical industry to control many serious phytopathogens. The phytotoxicity of the studied complexes also indicated their possibility as potential bio-based herbicides alternatives to weed control in crop fields.     

Synthesis and biological properties of substituted 1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acids

A series of substituted 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinoline carboxylic acids was synthesized and tested for their in vitro and in vivo antibacterial activity. The introduction of a methyl group at the 5-position of quinoline nucleus enhanced characteristically the antibacterial activity against Gram-positive bacteria, including Streptococcus pneumonia, which is a major pathogen in the respiratory tract infection, while retaining Gram-negative activity. Among them, 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride (grepafloxacin) exhibited potent in vitro antibacterial activity against Gram-positive bacteria such as Streptococcus pneumoniae and high in vivo efficacy on the experimental systemic infections caused by the Gram-positive and -negative bacteria tested. It also showed a high distribution to the lung and bronchoalveolar lavage fluid in comparison to reference drugs and is now undergoing clinical evaluation.     

Interactions of metal ions with two quinolone antimicrobial agents (cinoxacin and ciprofloxacin). Spectroscopic and X-ray structural characterization. Antibacterial studies

Several novel metal-quinolone compounds have been synthesized and characterized by analytical, spectroscopic and X-ray diffraction methods. The crystal structure of the four compounds, Na(2)[(Cd(Cx)3)(Cd(Cx)3(H2O))].12H2O, [Co(Cp)2(H2O)2].9H2O, [Zn(Cp)2(H2O)2].8H2O and [Cd(HCp)2(Cl)2].4H2O, is presented and discussed: HCx=1-ethyl-1,4-dihydro-4-oxo(1,3)-dioxolo(4,5-g)cinnoline-3-carboxylic acid and HCp=1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid. In all these compounds the quinolone acts as a bidentate chelate ligand that binds through one carboxylate oxygen atom and the exocyclic carbonyl oxygen atom. Complexes of ciprofloxacin were screened for their activity against several bacteria, showing activity similar to that of the ligand. In addition, the number of bacteria killed after 3 h of incubation with the ligand, [Co(Cp)2(H2O)2].9H2O, Ni(Cp)2.10H2O and Cu(Cp)2.6H2O, was determined against S. aureus ATCC25923. There is a direct relationship between the growth rate and the lethal rate. Against growing bacteria, the ligand is the most bactericidal and Cu(Cp)2.6H2O is the less bactericidal. On the contrary, against non-dividing bacteria, the complexes were more bactericidal than the ligand, with Cu(Cp)(2).6H(2)O the most bactericidal compound.     

Synthesis of pyrazinamide Mannich bases and its antitubercular properties

A series of pyrazinamide (PAZ) Mannich bases has been synthesized by reacting PAZ, formaldehyde, and various substituted piperazines using microwave irradiation with the yield ranging from 46% to 86%. The synthesized compounds were evaluated for antimycobacterial activity in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB). Among the synthesized compounds, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-4-((pyrazine-2-carboxamido)methyl)piperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (17) was found to be the most active compound in vitro with MIC of 0.39 and 0.2 microg/mL against MTB and multidrug-resistant MTB, respectively. In the in vivo animal model 17 decreased the bacterial load in lung and spleen tissues with 1.86 and 1.66-log10 protections, respectively.     

Synthesis, in vitro and in vivo antimycobacterial activities of diclofenac acid hydrazones and amides

Various diclofenac acid hydrazones and amides were synthesized and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis. Preliminary results indicated that most of the compounds demonstrated better in vitro antimycobacterial activity (MIC: 0.0383-7.53 microM) than diclofenac (MIC: 21.10 microM) and ciprofloxacin (MIC: 9.41 microM). Among the synthesized compounds, 1-cyclopropyl-6-fluoro-8-methoxy-7-[[N4-(2-(2-(2,6-dichlorophenylamino)phenyl)acetyl)-3-methyl]-N1-piperazinyl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (5d) was found to be the most active compound in vitro with MIC of 0.0383 microM and was more potent than first line antitubercular drug isoniazid (MIC: 0.1822 microM). In the in vivo animal model 5d decreased the bacterial load in lung and spleen tissues with 2.42- and 3.66-log10 protections, respectively, at 25 mg/kg body weight.     

Synthesis and antibacterial properties of new N4-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids

Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and primary α-amino acids (exemplified by glycine, alanine, and l-valine) in aqueous ethanolic NaHCO₃ at 70–80°C for 24–72?h produced the respective N-(4-oxoquinolin-7-yl)-α-amino acids (6a–c). The latter derivatives underwent reductive lactamization upon treatment with Na₂S₂O₄ in aqueous ethanol to afford moderate yields of the corresponding pyrido[2,3-f]quinoxaline-8-carboxylic acids (8a–c). Acetylation of 8a–c using acetyl chloride afforded N₄-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids (9a–c). The structures, assigned to these new heterocyclic products, are supported by analytical and spectral data. The synthesized compounds (6a–c/9a–c) showed appreciable antibacterial activity as compared with ciprofloxacin.     

Photodegradation of Fleroxacin Injection: Different Products with Different Concentration Levels

Photodegradation of fleroxacin is investigated in different injections and solutions. After UV irradiation, fleroxacin was degraded to afford two major products in large-volume injection (specification, 200 mg:100 ml), while degraded to afford another major product in small-volume injection (specification, 200 mg:2 ml). The photodegradation products were detected and isolated by reversed-phase HPLC. Based on the spectral data (FT-IR, MSⁿ, TOF-MS, ¹H/¹³C, DEPT, and 2D NMR), the structures of these products were: 8-fluoro-9-(4-methyl-piperazin-1-yl)-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid (impurity-I); 6-fluoro-1-(2-fluoro-ethyl)-7-(2-methylamino-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (impurity-II); and 6,8-difluoro-1-(2-fluoro-ethyl)-7-(2-methylamino-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (impurity-III), respectively. Different photodegradation pathways of fleroxacin were proposed, which led to the different stability characteristics of fleroxacin in the injections. The fluorine atom at C8 is more photolabile in dilute injection, so defluorination and cyclization reactions are prone to take place, whereas photo irradiation only cause ring-opening oxidation reaction of piperazine side chain in concentrated injection.     

Novel ofloxacin derivatives: synthesis, antimycobacterial and toxicological evaluation

Thirty novel 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from mycobacteria. Among the synthesized compounds, 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active compound in vitro with MIC99 of 0.19 microM and 0.09 microM against MTB and MTR-TB, respectively. In the in vivo animal model also the same compound decreased the bacterial load in lung and spleen tissues with 1.91 and 2.91--log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 10-[(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active in the inhibition of the supercoiling activity of DNA gyrase with an IC(50) of 10.0 microg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.     

Solution and solid-state studies of complexation of transition-metal cations and Al(III) by aroylhydrazones derived from nicotinic acid hydrazide

Reactions of first series transition-metal cations, Cd(II) and Al(III) with two aroylhydrazones derived from nicotinic acid hydrazide and salicylaldehyde or o-vanillin were studied at 25 °C in buffered dioxane/water 1/1 mixture (pH 5.8) by means of spectrophotometric and spectrofluorimetric titrations. The addition of Mn(II) or Cd(II) ions in hydrazone solutions had no effect on their absorption spectra whereas the addition of Ni(II) and Cr(III) immediately caused precipitation. The reaction of Zn(II) with salicylaldehyde derivative was found to be photosensitive. Relatively high conditional stability constants of 1:1 complexes of Cu(II), Zn(II) and Al(III) with both ligands were determined. Solid complexes of Cu(II), Ni(II) and Zn(II) with aroylhydrazones studied were isolated and characterized by elemental and thermogravimetric analyses, magnetic susceptibility measurements (in the case of Cu(II) and Ni(II)) and IR spectrometry.     

Complexation of desferricoprogen with trivalent Fe, Al, Ga, In and divalent Fe, Ni, Cu, Zn metal ions: effects of the linking chain structure on the metal binding ability of hydroxamate based siderophores

Complexes of the natural siderophore, desferricoprogen (DFC), with several trivalent and divalent metal ions in aqueous solution were studied by pH-potentiometry, UV-Vis spectrophotometry and cyclic voltammetry. DFC was found to be an effective metal binding ligand, which, in addition to Fe(III), forms complexes of high stability with Ga(III), Al(III), In(III), Cu(II), Ni(II) and Zn(II). Fe(II), however, is oxidized by DFC under anaerobic conditions and Fe(III) complexes are formed. By comparing the results with those of desferrioxamine B (DFB), it can be concluded that the conjugated beta-double bond slightly increases the stability of the hydroxamate chelates, consequently increases the stability of mono-chelated complexes of DFC. Any steric effect by the connecting chains arises only in the bis- and tris-chelated complexes. With metal ions possessing a relatively big ionic radius (Cu(II), Ni(II), Zn(II), In(III)) DFC, containing a bit longer chains than DFB, forms slightly more stable complexes. With smaller metal ions the trend is the opposite. Also a notable difference is that stable trinuclear complex, [Cu(3)L(2)], is formed with DFC but not with DFB. Possible bio-relevance of the Fe(II)/Fe(III) results is also discussed in the paper.     

Regioselective transformation of ciprofloxacin to N-acetylciprofloxacin by the fungus Mucor ramannianus

A strain of the saprobic fungus Mucor ramannianus, isolated from a forest, was used to demonstrate the potential for ciprofloxacin biotransformation by zygomycetes in the environment. The fungus carried out the regioselective N-acetylation of ciprofloxacin to a single product, which was purified from culture extracts by high-performance liquid chromatography. The metabolite was identified by mass and nuclear magnetic resonance spectrometry as 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-acetyl-1-piperazinyl)-3- quinolinecarboxylic acid.     

Electronic property and reactivity of (hydroperoxo)metal compounds

DFT calculations were done for the (hydroperoxo)metal complexes with eta1-coordination mode, where metal ions are Fe(III), Al(III), Cu(II) and Zn(II). Results shows that 1) the electron density at the two oxygen atoms of the hydroperoxide ion is highly dependent on the angle O-O-H in M-OOH species and the difference in electron density between the two oxygen atoms reaches a maximum at the angle O-O-H = 180 degrees, 2) total electron density at the two oxygen atoms of the peroxide ion increases by approach of methane to the (hydroperoxo)metal species in the cases of Fe(III) and Cu(II); on the other hand, significant decrease of the electron density on peroxide oxygen atoms was observed for the cases of Al(III) and Zn(II) compounds. These findings suggest that the (hydroperoxo)metal species acts as an electrophile in the former cases (M = Fe(III), Cu(II)) and as a nucleophile for the latter two compounds (M = Zn(II), Al(III)). The electrophilicity observed for the Fe(III) and Cu(II) complexes is attributed to the presence of unoccupied- or half-filled d-orbitals interacting with the hydroperoxide ion. 3) Two oxygen atoms of the (hydroperoxo)-compounds of Fe(III) and Cu(II) complexes exhibit quite different reactivity toward the substrate, such as methane. When methane approaches the oxygen atom which is coordinated to a metal ion, a strong decrease of electron density at the methane carbon atom occurs with concomitant increase of electron density at the peroxide oxygen atoms inducing its heterolytic O-O cleavage. When methane approaches the terminal oxygen atom, an oxidative coupling reaction occurs between peroxide ion and methane; at first a nucleophilic attack by the terminal electron-rich oxygen atom occurs at the carbon atom to induce C-O bond formation, and a subsequent oxidative electron transfer proceeds from substrate to the metal-peroxide species yielding CH3-OOH, CH3OH, or other oxidized products. These results clearly demonstrate that the (hydroperoxo)-metal compound itself is a rather stable compound, and activation of the peroxide ion is induced by interaction with the substrate, and the products obtained by the oxygenation reaction are dependent on the chemical property of the substrate, redox property of a metal ion, and stability of the compounds formed in the intermediate process.