Design and synthesis of an oral prodrug alalevonadifloxacin for the treatment of MRSA infection.

Levonadifloxacin is a parenteral anti-MRSA benzoquinolizine antibacterial drug recently launched as, EMROK in India to treat acute bacterial skin and skin structure infections (ABSSSI) in hospitalized patients. As a step down therapy an oral form of levonadifloxacin with comparable PK/PD was needed because the levonadifloxacin exhibits very poor oral absorption. To improve the drugability in terms of oral absorption a pro-drug approach was evaluated. Structurally levonadifloxacin provides two sites amenable for ester or amide formation, a carboxyl function of benzoquinolizine pharmacophore and hydroxyl group on piperidine side chain. Several aliphatic, aromatic and amino acid esters of C-2 carboxylic acid, C-4-hydroxyl piperidine and double esters at both C-2, C-4 positions were synthesized. The cleavage of prodrugs was studied in vitro as well as in animal models to access their suitability as prodrug function. Among C-2 carboxylic ester prodrugs, daloxate (WCK 2320) showed highest cleavage in serum as well as in liver enzyme; however its stability in aqueous solution was unfavorable. In contrast, most of the esters at the hydroxyl group like propionyl ester (WCK 2305) and amino acid esters such as l-alanine (WCK 2349), l-valine (WCK 2630) were cleaved readily releasing active drug. Thus, indicating C-4-hydroxyl piperidine was amenable site for enzymatic cleavage over esters of C-2 carboxylic acid. Additionally, amino acid esters provided an opportunity to make salt, facilitating improved aqueous solubility. Methanesulfonate salt of l-alanine ester of levonadifloxacin (WCK 2349) was successfully developed and launched as oral prodrug alalevonadifloxacin (EMROK-O).

Moxifloxacin-Ester derivatives: Synthesis, characterization and pharmacological evaluation.

It is known that resistance of bacteria is one of the major issues in drug treatment. To cope this issue, it is required to synthesize new analogues which contest against mutated bacteria. This research study included synthesis of several derivatives of moxifloxacin by adding different phenol and alkyl halide at third position of carboxylic group with esterification reaction and the structures of synthesized derivatives were characterized by spectroscopic techniques i.e. 1H NMR, FT-IR and mass-spectrometry. In continuation, antimicrobial activities of the analogues were also evaluated against number of Gram-positive, Gram-negative bacteria and fungi. The experimental results of novel derivatives exhibit significant antibacterial and antifungal profile in which so many synthesized derivatives influenced a similar and enhanced activity against selected microbes that were S. typhi, P. mirabilis, P. aeruginosa, S. flexneri, B. subtilis as compared to the moxifloxacin. Moreover, few innovative derivatives were also produced better anti-fungal activity against F. solani and T. rubrum. Furthermore, the enzymatic activity of all analogues has been analyzed against urease and carbonic anhydrase and concluded that C2 was selected inhibitor of urease enzyme.

New fluoroquinolone compounds with endo-nortropine derivatives at C-7 position show antibacterial activity against fluoroquinolone-resistant strains of Staphylococcus aureus.

A series of new fluoroquinolone analogs (3-18) were prepared, in three steps, by substituting chloro esters and esters with cyclic amines on the C-7 endo-nortropine derivatives of difluoroquinolone acid. All the synthesized compounds displayed good MIC against the Staphylococcus aureus when initially screened for Escherichia coli, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. The molecules were further evaluated for their antibacterial activity against fluoroquinolone-resistant strains of S. aureus and for cytotoxic assay. Based on the results, five of the sixteen compounds displayed the potential to be developed further for treatment against fluoroquinolone-resistant strains of S. aureus.

Synthesis and in vitro antibacterial activity of 7-(3-alkoxyimino-4-amino-4-methylpiperidin-1-yl) fluoroquinolone derivatives.

A series of novel 7-(3-alkoxyimino-4-amino-4-methylpiperidin-1-yl)fluoroquinolone derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cytotoxicity. All of the target compounds have potent antibacterial activity against the tested Gram-positive and Gram-negative strains, and exhibit good potency in inhibiting the growth of Staphylococcus aureus including MRSA, Staphylococcus epidermidis including MRSE and Streptococcus pneumoniae (MICs: 0.125-4 µg/mL). Compound 22, with the best activity against Gram-positive strains, is 4-16 fold more potent than gemifloxacin, gatifloxacin and levofloxacin against Enterococcus faecalis, and 16- and 4-fold more potent than levofloxacin against S. epidermidis 09-6 and S. pneumoniae 08-4, respectively.

Solution and biological behaviour of enrofloxacin metalloantibiotics: a route to counteract bacterial resistance?

Solution behaviour of enrofloxacin complexes with copper(II), nickel(II), cobalt(II) and zinc(II) in the presence and absence of 1, 10-phenanthroline was studied in aqueous solution, by potentiometry. The results obtained show that under physiological conditions (micromolar concentration range and pH 7.4) only copper(II) forms stable complexes. Binary copper(II)/enrofloxacin and ternary copper(II)/enrofloxacin/phenanthroline complexes were synthesised and characterized by elemental analysis, UV-visible spectroscopy and FTIR. The antimicrobial activity of these complexes and of copper(II)/enrofloxacin and copper(II)/enrofloxacin/phenanthroline solutions, prepared by mixing of the individual components in the same stoichiometric proportion and concentration range used for the synthesised complexes, was tested against two different Escherichia coli strains. Although, at a glance, the results point to a possible use of both complexes as metalloantibiotics, a detailed analysis shows that, at biological concentrations, the copper(II) binary complex does not exist and the antimicrobial activity observed is a consequence of its dissociation into free enrofloxacin. Consequently, only the ternary complex seems worth pursuing as a possible antimicrobial agent candidate. Moreover, as the biological studies showed, both the synthesised complexes and the solutions prepared by mixing the components exhibited the same behaviour. Hence, a new, faster and accurate methodology to screen metalloantibiotics prior to synthesis of the complexes is proposed.

Phenothiazinium-fluoroquinolone drug conjugates.

Synthesis and antibacterial screening of a homologous series of 3-dialkylaminophenothiazinium-7-norfloxacin conjugates was carried out alongside a corresponding series of symmetrical methylene blue derivatives. The norfloxacin conjugates maintained typical methylene blue derivative photoproperties, such as long wavelength absorption, but produced no measurable singlet oxygen in the standard assay and provided no significant increase in the magnitude of photoantibacterial action, this being similar to the methylene blue homologues, although both the conjugates and homologues were considerably more active than methylene blue itself both against Staphylococcus aureus and Escherichia coli. DNA binding via intercalation was considerably greater for the series of norfloxacin conjugates than for the methylene blue homologues.

Metalloantibiotics: synthesis, characterization and antimicrobial evaluation of bismuth-fluoroquinolone complexes against Helicobacter pylori.

Novel organometallic compounds have been prepared by complexing the fluoroquinolones, norfloxacin, ofloxacin, ciprofloxacin, sparfloxacin, lomefloxacin, pefloxacin and gatifloxacin, with bismuth. The complexes were characterized by UV, IR, atomic absorption spectroscopy, elemental analysis, differential scanning calorimetry, thermogravimetric analysis and mass spectrometry. Their antibacterial potential against Helicobacter pylori and other microorganisms was investigated. These compounds were found to possess strong activity against Helicobacter pylori with a minimum inhibitory concentration of 0.5 mg L-1. They also exhibited moderate activity against Escherichia coli, Staphylococcus aureus, Bacillus pumilus and Staphylococcus epidermidis. These bismuth-fluoroquinolone complexes have the potential to be developed as drugs against H. pylori related ailments.

Synthesis and in-vitro cytotoxicity evaluation of gatifloxacin Mannich bases.

Mannich bases of gatifloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. The compounds were tested in-vitro against a panel of 58 human tumour cell lines derived from nine neoplastic diseases. Among them compound 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7[[N4-(3'-sulphadoximino)-1'-(5-bromoisatinyl) methyl]-3-methyl N1-piperazinyl]-3-quinoline carboxylic acid (6) emerged as a potent anticancer agent being more active than standard DNA topoisomerase II inhibitor, etoposide against 30 cancer cell lines.

Relación estructura-fotoestabilidad u fototoxicidad de fluoroquinolonas / Structure-photostability and phototoxicity relationship in fluoroquinolones

Las quinolonas constituyen una familia de antibióticos de amplio uso en la actualidad, debido a su gran eficacia clínica en el tratamiento de infecciones del tracto respiratorio, urinario, tejidos blandos y enfermedades de transmisión sexual. De acuerdo a su estructura base se pueden clasificar en quinolonas naftiridínicas (enoxacino y ácido nalidíxico), quinolínicas (ciprofloxacino, norfloxacino, ácido oxolínico, rosoxacino) y pirimido-pirimidinicas (ácido pipemídico). Las quinolonas se caracterizan por presentar reacciones de fotosensibilidad y fotolabilidad. El ácido nalidíxico, quinolona de primera generación, presenta reacciones de fototoxicidad, evaluadas en el modelo del glóbulo rojo y en cultivos celulares. El ácido nalidíxico, exento del sustituyente piperazínico presenta una fotolabilidad disminuida. Las fluoroquinolonas, a diferencia del ácido nalidíxico, presentan un anillo piperazínico o metil piperazínico en posición 7, incorporado con el fin de mejorar las propiedades antibacterianas. En este trabajo se investiga la influencia del anillo piperazínico en posición 7 sobre la fotolabilidad y fototoxicidad, demostrándose que las fluoroquinolonas que poseen este sustituyente presentan una fotolabilidad aumentada y una fototoxicidad disminuída, en relación a quinolonas carentes de éste grupo. Es probable que la fotodegradación de quinolonas transcurra mediante un mecanismo radicalario, con la pérdida del grupo carboxílico

Quinolones constitute a large class of synthetic antimicrobial agents that are highly effective in the treatment of respiratory, urinary, sexually transmitted diseases and soft tissue infection. In agreement with his structure the quinolones can be classified into naftaridines (enoxacin and nalidixic acid), quinolines (ciprofloxacin, norfloxacin, oxolinic acid, roxosacin) and pyrid-pyrimidin (pipemidic acid). Some quinolones may undergo photodegradation reactions. On the other hand, quinolones can induce cutaneous photosensitivity reactions.and photolability as well. Nalidixic acid, a first quinolone generation, may undergo phototoxic effects on the red blood cells and in cell culture. Nalidixic acid, which has not the piperazine group in position 7, exhibit a moderated photolability. The fluoroquinolones as oppossed to nalidixic acid have a piperazine ring in position 7. We investigated the influence of the piperazine ring on the phototoxicity and photolability of several quinolones. We demonstrated that the fluoroquinolones with piperazinic group present higher photolability and less phototoxicity .It is possible that the photodegradation of quinolones takes place through a radical pathway, with the loss of a carboxylic acid group

New 6-nitroquinolones: synthesis and antimicrobial activities.

Pursuing our searches on quinolonecarboxylic acids we used a simple three-step one pot procedure to synthesize novel 1,7-disubstituted-6-nitroquinolones. The new derivatives were tested against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) as well as against both gram-positive and gram-negative bacteria. In vitro assays showed some derivatives were endowed with good inhibiting activities against tested mycobacteria. Some derivatives were also found more potent than ciprofloxacin and ofloxacin (used as reference drugs) against gram-positive bacteria.

Gemifloxacin: a new fluoroquinolone.

Gemifloxacin is a dual targeted fluoroquinolone with potent in vitro activity against Gram-positive, -negative and atypical human pathogens--pathogens considered to be important causes of community-acquired respiratory tract infections. Gemifloxacin demonstrates impressive minimal inhibitory concentrations (MIC 90 ) values against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydia pneumoniae and Legionella spp., with MIC 90 values reported to be 0.016-0.06, < 0.0008-0.06, 0.008-0.3, 0.25, 0.125 and 0.016-0.07 microg/ml, respectively. Gemifloxacin is also active in vitro against a broad range of Gram-negative bacilli with MIC 90 values against the Enterobacteriaceae in the range of 0.016 to > 16 microg/ml ( Escherichia coli and Providencia stuartii, respectively), with the majority of the genus having MIC 90 drug concentrations < 0.5 microg/ml. The in vitro activity of gemifloxacin against anaerobic organisms is variable. The MIC values for gemifloxacin are not affected by beta-lactamase production nor by penicillin or macrolide resistance in S. pneumoniae. Gemifloxacin is approved by the FDA to be clinically efficacious against multi-drug resistant S. pneumoniae. The pharmacokinetics of gemifloxacin are such that the drug can be administered orally once-daily to yield or achieve sustainable drug concentrations exceeding the MIC values of clinically important organisms. Gemifloxacin has been shown to target both DNA gyrase (preferred target) and topoisomerase IV (secondary target) - enzymes critical for DNA replication and organism survival - against clinical isolates of S. pneumoniae. This dual targeting activity is thought to be important for reducing the likelihood for selecting for quinolone resistance. Gemifloxacin has been investigated and approved for therapy in patients with community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis. In one study, more patients receiving gemifloxacin compared to clarithromycin remained free of exacerbations for longer periods of time (p < 0.016) and gemifloxacin had a shorter time to eradication of H. influenzae than did clarithromycin (p < 0.02). From efficacy studies, gemifloxacin was found to have an adverse profile that was comparable with other compounds. The most frequent side effects were diarrhoea, abdominal pain and headache. Gemifloxacin is a welcomed addition to currently available agents for the treatment of community-acquired lower respiratory tract infections. Other potential indications appear to be within the spectrum of this compound.

Syntheses and biological evaluation of new fluoroquinolone antibacterials containing chiral oxiimino pyrrolidine.

The design and syntheses of new fluoroquinolone antibacterial agents having pyrrolidine ring at C-7 position are described. The pyrrolidine ring is optically active and possesses methyloxime functional group. Two of them have excellent in vitro antibacterial activities and pharmacokinetic profiles.