Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents 2. Modification of the phenyl ring — the potentiating effect of fluorine substitution on in vivo activity

Barbachyn, Michael R.; Toops, Dana S.; Grega, Kevin C.; Hendges, Susan K.; Ford, Charles W.; Zurenko, Gary E.; Hamel, Judith C.; Schaadt, Jonda D.; Stapert, Douglas; Yagi, Betty H.; Buysse, Jerry M.; Demyan, W. F.; Kilburn, James O.; Glickman, Suzanne E.

doi:10.1016/0960-894x(96)00155-2

Cited by 25 publications

(11 citation statements)

References 6 publications

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“…A lead compound can be defined as a compound that displays pharmacological parameters proposing the compound’s value as a starting point for therapeutics development. 2 Further structural discussion led to the development of piperazine derivatives using lead compounds, as shown in studies by Barbachyn et al 2 Such compounds were selected for further modification as they possessed outstanding antibacterial activity with a suitable safety profile. Linezolid was introduced in 1996 following intensive examinations at Pharmacia 3 and has since been identified as a lead compound.…”

Section: Introductionmentioning

confidence: 99%

Linezolid: a review of its properties, function, and use in critical care

Hashemian¹,

Farhadi²,

Ganjparvar³

2018

DDDT

280

193

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Linezolid can be considered as the first member of the class of oxazolidinone antibiotics. The compound is a synthetic antibiotic that inhibits bacterial protein synthesis through binding to rRNA. It also inhibits the creation of the initiation complex during protein synthesis which can reduce the length of the developed peptide chains, and decrease the rate of reaction of translation elongation. Linezolid has been approved for the treatment of infections caused by vancomycin-resistant Enterococcus faecium, hospital-acquired pneumonia caused by Staphylococcus aureus, complicated skin and skin structure infections (SSSIs), uncomplicated SSSIs caused by methicillin-susceptible S. aureus or Streptococcus pyogenes, and community-acquired pneumonia caused by Streptococcus pneumoniae. Analysis of high-resolution structures of linezolid has demonstrated that it binds a deep cleft of the 50S ribosomal subunit that is surrounded by 23S rRNA nucleotides. Mutation of 23S rRNA was shown to be a linezolid resistance mechanism. Besides, mutations in specific regions of ribosomal proteins uL3 and uL4 are increasingly associated with linezolid resistance. However, these proteins are located further away from the bound drug. The methicillin-resistant S. aureus and vancomycin-resistant enterococci are considered the most common Gram-positive bacteria found in intensive care units (ICUs), and linezolid, as an antimicrobial drug, is commonly utilized to treat infected ICU patients. The drug has favorable in vitro and in vivo activity against the mentioned organisms and is considered as a useful antibiotic to treat infections in the ICU.

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Section: Introductionmentioning

confidence: 99%

Linezolid: a review of its properties, function, and use in critical care

Hashemian¹,

Farhadi²,

Ganjparvar³

2018

DDDT

280

193

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“…However, the co-generation of these reactive intermediate alkylating species, along with the byproduct benzyl iodide itself, might be expected to represent a serious limitation with various heterocyclic substrates, in particular, N- allyl N- heteroaryl carbamates bearing a basic nitrogen atom. Indeed, an early application of iodocyclocarbamation reaction conditions to allylated pyridin-3-yl- and pyridin-4-ylphenyl carbamates was reported to completely fail because of the significant N -benzylation of the basic nitrogen atom in these systems . A measure of success was ultimately achieved in this prior work through the introduction of excess pyridine into the CHCl 3 -based reaction medium to serve as an effective benzyl iodide scavenger.…”

Section: Resultsmentioning

confidence: 97%

“…The first example of an iodocyclocarbamation reaction involving an allylated N -aryl carbamate was reported by Brickner and co-workers and involved the iodine-mediated conversion of N -indolinyl allylic carbamate 1 to the corresponding racemic 3-(indolin-5-yl)-5-(iodomethyl)oxazolidin-2-one 2 in a 77% isolated yield (Scheme ). In two subsequent papers, focused on the regioselective metalation of stabase-protected anilines and palladium-mediated cross-coupling reactions with trimethylstannyltropones, the iodocyclocarbamation reaction was briefly described . A few more recent papers describing N -4-pyridyl, N -3-thienyl, and N -1-quinolin-4-yl allylic carbamates as substrates in the iodocyclocarbamation reaction have appeared but, again, generally not as the primary emphasis of the described research.…”

Section: Introductionmentioning

confidence: 99%

The Synthesis of Functionalized 3-Aryl- and 3-Heteroaryloxazolidin-2-ones and Tetrahydro-3-aryl-1,3-oxazin-2-ones via the Iodocyclocarbamation Reaction: Access to Privileged Chemical Structures and Scope and Limitations of the Method

et al. 2020

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3-Aryl- and 3-heteroaryloxazolidin-2-ones, by virtue of the diverse pharmacologic activities exhibited by them after subtle changes to their appended substituents, are becoming increasingly important and should be considered privileged chemical structures. The iodocyclocarbamation reaction has been extensively used to make many 3-alkyl-5-(halomethyl)oxazolidin-2-ones, but the corresponding aromatic congeners have been relatively underexplored. We suggest that racemic 3-aryl- and 3-heteroaryl-5-(iodomethyl)oxazolidin-2-ones, readily prepared by the iodocyclocarbamation reaction of N-allylated N-aryl or N-heteroaryl carbamates, may be useful intermediates for the rapid preparation of potential lead compounds with biological activity. We exemplify this point by using this approach to prepare racemic linezolid, an antibacterial agent. Herein, we report the results of our systematic investigation into the scope and limitations of this process and have identified some distinguishing characteristics within the aryl/heteroaryl series. We also describe the first preparation of 3-aryloxazolidin-2-ones bearing new functionalized C-5 substituents derived from conjugated 1,3-dienyl and cumulated 1,2-dienyl carbamate precursors. Finally, we describe the utility of the iodocyclocarbamation reaction for making six-membered tetrahydro-3-aryl-1,3-oxazin-2-ones.

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“…1, [9]); and (3) the troponyl phenyl oxazolidinones, exemplified by PNU‐97786 (Fig. 1, [10]) 12,15–17 . The indolines generally exhibited an excellent safety profile, but demonstrated somewhat lower levels of antibacterial activity than desired.…”

Section: The First Clinically Useful Oxazolidinone Linezolidmentioning

confidence: 99%

“…The Upjohn group's principal contributions to advancing an understanding of oxazolidinones SAR include (1) the finding that one or two fluorine atoms flanking the substituent in the para position on the phenyl ring usually exerts a significant potentiating effect on antibacterial activity and/or efficacy, 12 , 17–21 and (2) an electron‐donating amino substituent in the para position on the phenyl ring often confers a good safety profile while maintaining excellent antibacterial activity 12,15 , 18–24 . The piperazinyl phenyl oxazolidinone SAR optimization program showed that a wide range of alkyl, carbonyl, and sulfonyl substituents were tolerated on the distal piperazine nitrogen atom 18,19,21 .…”

Section: The First Clinically Useful Oxazolidinone Linezolidmentioning

confidence: 99%

The oxazolidinones: past, present, and future

Shaw

Barbachyn

2011

Annals of the New York Academy of Sciences

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231

148

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The success of linezolid stimulated significant efforts to discover new agents in the oxazolidinone class. Over a dozen oxazolidinones have reached the clinic, but many were discontinued due to lack of differentiated potency, inadequate pharmacokinetics, and safety risks that included myelosuppression. Four oxazolidinones are currently undergoing clinical evaluation. The Trius Therapeutics compound tedizolid phosphate (formerly known as torezolid phosphate, TR-701, DA-7218), the most advanced, is in phase 3 clinical trials for acute bacterial skin and skin structure infections. Rib-X completed two phase 2 studies for radezolid (Rx-01_667, RX-1741) in uncomplicated skin and skin structure infections and community-acquired pneumonia. Pfizer and AstraZeneca have each identified antitubercular compounds that have completed phase 1 studies: sutezolid (PNU-100480, PF-02341272) and AZD5847 (AZD2563), respectively. The oxazolidinones share a relatively low frequency of resistance largely due to the requirement of mutations in 23S ribosomal RNA genes. However, maintaining potency against strains carrying the mobile cfr gene poses a challenge for the oxazolidinone class, as well as other 50S ribosome inhibitors that target the peptidyl transferase center.

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Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents 2. Modification of the phenyl ring — the potentiating effect of fluorine substitution on in vivo activity

Cited by 25 publications

References 6 publications

Linezolid: a review of its properties, function, and use in critical care

Linezolid: a review of its properties, function, and use in critical care

The Synthesis of Functionalized 3-Aryl- and 3-Heteroaryloxazolidin-2-ones and Tetrahydro-3-aryl-1,3-oxazin-2-ones via the Iodocyclocarbamation Reaction: Access to Privileged Chemical Structures and Scope and Limitations of the Method

The oxazolidinones: past, present, and future

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