Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents 1. Identification of leads and importance of the tropone substitution pattern

Barbachyn, Michael R.; Toops, Dana S.; Ulanowicz, Debra A.; Grega, Kevin C.; Brickner, Steven J.; Ford, Charles W.; Zurenko, Gary E.; Hamel, Judith C.; Schaadt, Ronda D.; Stapert, Douglas; Yagi, Betty H.; Buysse, Jerry M.; Demyan, W. F.; Kilburn, James O.; Glickman, Suzanne E.

doi:10.1016/0960-894x(96)00154-0

Cited by 17 publications

(13 citation statements)

References 14 publications

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“…Palladium catalyzed hydrogenation of compound 5 followed by reaction with CbzCl gave protected aniline 6 . Then, as reported, 7a compound 6 was sequentially treated with n BuLi and R -glycidyl butyrate at −78 °C to form the key oxazolidinone 7 in 71% yield with defined stereochemistry at the C-5 position of ring A. Reaction of 7 with acetic anhydride in the presence of DMAP and pyridine afforded the corresponding C-5 acetate analog, 8 , in 95% yield.…”

Section: Resultsmentioning

confidence: 95%

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Syntheses and biological evaluation of new cephalosporin-oxazolidinone conjugates

et al. 2010

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Section: Resultsmentioning

confidence: 95%

“…The syntheses utilized considerable literature precedent 7 and began with a S N Ar reaction of 3,4-difluoronitrobenzene and mono Boc-protected piperazine 4 to afford para -substituted nitrobenzene derivative 5 in 49% yield. Palladium catalyzed hydrogenation of compound 5 followed by reaction with CbzCl gave protected aniline 6 .…”

Section: Resultsmentioning

confidence: 99%

Syntheses and biological evaluation of new cephalosporin-oxazolidinone conjugates

et al. 2010

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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 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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“…Tropones and troponoids are interesting compounds due to their anticancer properties, , antimicrobial activity, , and antifungal effects . The oxidation of the exocyclic carbon–carbon double bond of a heptafulvene by meta -chloroperoxybenzoic acid ( m CPBA) provides an unusually mild method for obtaining tropones. , Understanding the mechanism of this reaction would allow for optimizing the reaction conditions to obtain the maximal yield of the desired product and minimal formation of byproducts.…”

Section: Introductionmentioning

confidence: 99%

“…Tropones and troponoids are interesting compounds due to their anticancer properties, 1,2 antimicrobial activity, 3,4 and antifungal effects. 5 The oxidation of the exocyclic carbon− carbon double bond of a heptafulvene by meta-chloroperoxybenzoic acid (mCPBA) provides an unusually mild method for obtaining tropones.…”

Section: ■ Introductionmentioning

confidence: 99%

Mechanism of the Oxidation of Heptafulvenes to Tropones Studied by Online Mass Spectrometry and Density Functional Theory Calculations

et al. 2019

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We have identified the most likely reaction mechanism for oxidizing heptafulvenes to the corresponding tropones by experimental and theoretical investigations. The experimental studies were done by coupling a three-dimensional printed miniaturized reactor with an integrated electrospray ionization needle to a mass spectrometer. Using the experimentally observed ions as a basis, nine alternative reaction pathways were investigated with density functional theory calculations. The lowest energy reaction pathway starts with the formation of an epoxide that is opened upon the addition of a second equivalent of the oxidizing species meta-chloroperoxybenzoic acid. The adduct formed then undergoes a Criegee-like rearrangement to yield a positively charged hemiketal, which on deprotonation dissociates into acetone and tropone. Overall, the reaction mechanism resembles a Hock-like rearrangement.

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Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents 1. Identification of leads and importance of the tropone substitution pattern

Cited by 17 publications

References 14 publications

Syntheses and biological evaluation of new cephalosporin-oxazolidinone conjugates

Syntheses and biological evaluation of new cephalosporin-oxazolidinone conjugates

The oxazolidinones: past, present, and future

Mechanism of the Oxidation of Heptafulvenes to Tropones Studied by Online Mass Spectrometry and Density Functional Theory Calculations

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