Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity

Sanchez, Joseph P.; Domagala, John M.; Heifetz, Carl L.; Priebe, Stephen R.; Sesnie, Josephine A.; Trehan, Ashok K.

doi:10.1021/jm00088a011

Cited by 38 publications

(16 citation statements)

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“…Optically pure 3-aminopyrrolidine (3AP) and 3-aminopiperidine (3APi) (Scheme 1) have become attractive synthons for the synthesis of a broad range of biologically active pharmaceuticals such as Tosufloxacin, Clinafloxacin [1] and cephalosporin derivatives. [2] Other compounds containing a 3AP-or 3APi-residue are interesting for the treatment of obesity [3] , diabetes mellitus types I and II [4] or as psychotropic drugs against depression and schizophrenia.…”

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confidence: 99%

“…There are three different synthetic routes: substitution, cyclization and classical resolution of the racemate with resolving agents. Most of them have one ore more drawbacks: substitution reactions via azide displacement [1,6] require 1-N-protected mesylated or tosylated alcohol, which is either expensive or must be prepared via multistep syntheses. Furthermore, the substitution proceeds via an inversion of the configuration, so that an unwanted non-selective S N 1-reaction has to be avoided.…”

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confidence: 99%

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A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

2008

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The kinetic resolution of 3-aminopyrrolidine (3AP) and 3-aminopiperidine (3APi) with wtransaminases was facilitated by the application of a protecting group concept. 1-N-Cbz-protected 3-aminopyrrolidine could be resolved with > 99% ee at 50% conversion, the resolution of 1-N-Boc-3-aminopiperidine yielded 96% ee at 55% conversion. The reaction rate was up to 50-fold higher by using protected substrates. Most importantly, enantioselectivity increased remarkably after carbamate protection compared to the unprotected substrates (86 vs. 99% ee). Surprisingly, benzyl protection of 3AP had no influence on enantioselectivity. A possible explanation for this observation could be the different flexibility of the benzyl-or carbamate-protected 3AP as confirmed by NMR spectroscopy.

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A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

2008

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“…Studies on prokaryotic systems demonstrate that DNA gyrase can discern the stereoconfiguration of ring substituents in chiral quinolones (5,7,10,12,15,21,30,32). With regard to ofloxacin, the bacterial enzyme displays a high (210-fold) specificity for the S over the R configuration at the C-11 position (5,7,10,12,15,21).…”

Section: Discussionmentioning

confidence: 99%

Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme

Froelich-Ammon

McGuirk

Gootz

et al. 1993

Antimicrob Agents Chemother

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A series of novel C-7 quinolyl-substituted enantiomers of ofloxacin were used to determine the stereospecificity of topoisomerase II for the C-il methyl group in tricyclic quinolones. In all cases, the S isomer was the most active compound against the eukaryotic enzyme. It was -2.2-fold more potent than the R isomer at inhibiting the overall catalytic activity of topoisomerase II (as monitored by DNA relaxation assays). A markedly greater difference in quinolone activity was observed in enzyme-mediated DNA cleavage reactions.While the S enantiomer stimulated nucleic acid breakage -3.5-fold, the R compound did not enhance and, in fact, decreased initial DNA cleavage levels by -50%o. The activity of the racemic mixture more closely resembled that of the R enantiomer. In competition experiments, the DNA cleavage-enhancing effects of the S isomer were attenuated by the R compound. Taken together, these latter results indicate that the R enantiomer is an antagonist of S isomer-promoted topoisomerase II-mediated DNA cleavage. Finally, the cytotoxic potential of quinolyl-substituted ofloxacin analogs correlated with the ability to stimulate enzyme-mediated DNA cleavage. Thus, stereochemistry appears to be a governing factor for the potential development of tricyclic quinolones as topoisomerase II-targeted drugs with antineoplastic activity.Quinolone-based drugs are a widely used class of oral antibiotics (11,37,42). The primary physiological target of these important pharmacological agents is DNA gyrase, a prokaryotic type II topoisomerase (11,27,36,42). Quinolones cause bacterial death by converting DNA gyrase into a cellular poison (18). This is accomplished by stabilizing covalent enzyme-cleaved DNA complexes (6,11,35) which are naturally occurring intermediates in the catalytic cycle of all type II topoisomerases (26,27).While most medically relevant quinolones have a bicyclic parent ring structure, ofloxacin (see Fig. 1), one of the most potent members of this drug family currently in clinical use, is tricyclic in nature (3,38). Unlike its bicyclic counterparts, the methyl-substituted 1-8 oxazine bridge of ofloxacin possesses a chiral center. This center, which is located at the C-il position, is indicated in Fig. 1. Although the clinical formulation of ofloxacin is a racemic mixture, enantiomerically pure R and S stereoisomers have been characterized (5,7,10,12,15,21). In all cases, the S isomer was substantially more active (.10-fold) than its R antipode at inhibiting the DNA supercoiling reaction of gyrase or preventing the growth of bacterial cells. The activity of the racemic ofloxacin generally was one-half that of the pure S isomer (5,7,10,12,15,21). Thus, it appears that the R enantiomer interacts poorly (at best) with DNA gyrase.The effects of ofloxacin enantiomers on the catalytic activity of eukaryotic topoisomerase II also have been examined (12). As determined by the inhibition of enzymecatalyzed DNA relaxation, an approximately twofold stereospecificity for the S configuration over the R configuratio...

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“…Pyridonecarboxylic acid derivatives with 1-or 2-naphthyl substituents at N-1 position showed potent in vitro anti-HIV activities with some compounds possessing even better activity than that of atevirdine [65]. BMS-A78277, 5,10-dihydrobenzo[beta] [1,8]naphthyridine-Noxide (44), belongs to the class of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which demonstrated improved activity profile against mutants of HIV-1 with pharmacokinetic profiles amenable to once-daily dosing. Biotransformation of this NNRTI candidate was studied by Daniels et al [66] in cynomolgus monkey model.…”

Section: Antiviral Activity (Hiv/hcv)mentioning

confidence: 99%

1,8‐Naphthyridine Derivatives: A Review of Multiple Biological Activities

Madaan

Verma

Kumar

et al. 2015

Archiv der Pharmazie

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The 1,8-naphthyridine group of compounds have gained special attention of researchers on account of their demonstrating a variety of interesting biological activities. A wide range of biological properties establishes them as potent scaffolds in therapeutic and medicinal research. The broad spectrum of activities primarily includes antimicrobial, antiviral, anticancer, anti-inflammatory, and analgesic activities. 1,8-Naphthyridine derivatives have also exhibited potential applications in neurological disorders such as Alzheimer's disease, multiple sclerosis, and depression. In addition, these synthetic derivatives have been found to possess activities such as anti-osteoporotic (α(v)β(3) antagonists), anti-allergic, antimalarial, gastric antisecretory, bronchodilator, anticonvulsant, anti-hypertensive, platelet aggregation inhibition, anti-oxidant, EGFR inhibition, protein kinase inhibition, ionotropic agent, β-3 antagonist, MDR modulator, adenosine receptor agonist, adrenoceptor antagonist, and pesticide activities. In spite of the widespread application of the 1,8-naphythyridine scaffolds, only a limited number of review articles are available till date. In this review, we attempt to compile and discuss the key data available in the literature for the multiple biological activities of 1,8-naphthyridine derivatives, in a chronological manner. This review compilation (with 199 references) may be helpful in understanding the diverse biological properties of 1,8-naphthyridines and provide insights into their mechanism of action. This may direct future research in the synthesis of new derivatives and exploring this scaffold for other possible biological activities.

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Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity

Cited by 38 publications

References 1 publication

A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme

1,8‐Naphthyridine Derivatives: A Review of Multiple Biological Activities

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