New classes of antibacterial oxazolidinones with C-5, methylene O-Linked heterocyclic side chains

Gravestock, Michael B.; Acton, David; Betts, Michael J.; Dennis, Michael Robert; Hatter, Glenn; McGregor, Alexandra; Swain, Michael L.; Wilson, R. Geoffrey; Woods, Lisa; Wookey, Alan

doi:10.1016/j.bmcl.2003.07.033

Cited by 57 publications

(16 citation statements)

References 17 publications

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“…Previous investigations from AstraZeneca have shown that AZD is active in an ex vivo model (14) and in an in vivo model using H37Rv (23), indicating that, like PNU, this oxazolidinone can cross the eukaryotic cell membrane and thus reach the bacteria engulfed in the macrophages. PNU, the active metabolite of PNU, and LZD are 52%, 89%, and 69% free in human plasma, respectively, in contrast to AZD, which is 20% free (24,25). Therefore, the relatively poor efficacy of AZD in the SS18b model compared to LZD or PNU could be due to differences in exposure to free drug at the target site.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of Three Oxazolidinones against Nonreplicating Mycobacterium tuberculosis

Zhang

Sala

Dhar

et al. 2014

Antimicrob Agents Chemother

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cOxazolidinones represent a new class of antituberculosis drugs that exert their function by inhibiting protein synthesis. Here, we compared the activities of three oxazolidinones, linezolid, PNU-100480, and AZD5847, against latent tuberculosis using a simple model employing the streptomycin-starved Mycobacterium tuberculosis strain 18b. The in vitro drug susceptibility results showed that the three oxazolidinones had a bacteriostatic effect against actively growing bacilli but potent bactericidal activity against nonreplicating cells. In the murine model of latent infection with M. tuberculosis 18b, the efficacy of the three compounds varied greatly. Indeed, AZD5847 or its prodrug exhibited no activity or only modest activity, respectively, after 2 months of treatment, whereas both linezolid and PNU-100480 were effective against latent bacilli in mice and showed promising outcomes in combination therapy with rifampin. Moreover, the potency of PNU-100480 was significantly greater than that of linezolid, making it an attractive drug candidate in the development of new combination therapies for latent tuberculosis. Despite the availability of effective chemotherapy, tuberculosis (TB) is still a major global health problem, and Ͼ8.6 million cases of active disease and 1.4 million deaths were reported in 2012 (1). Moreover, approximately one-third of the world's population is latently infected with Mycobacterium tuberculosis and at risk of reactivation (1). The slow growth and dormancy of M. tuberculosis contribute to the chronic nature of the infection, and effective treatment of active disease requires lengthy multidrug regimens. This situation is now worsened by the increasing emergence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and even totally drug-resistant M. tuberculosis strains (1), thus underscoring the urgent need for new molecules with potent activity against latent M. tuberculosis and no cross-resistance with existing therapeutic agents.Oxazolidinones are one of the only three new classes of antibiotics that have been approved by the Food and Drug Administration (FDA) in the last 35 years (2). Oxazolidinones inhibit bacterial protein synthesis via competitive binding to the 23S rRNA in the catalytic site of the bacterial 50S ribosomes (3, 4). Linezolid (LZD), the first oxazolidinone that entered clinical use, exhibits bacteriostatic activity against M. tuberculosis with an MIC of less than 1 g/ml (5) and has been used against MDR/XDR TB cases (4, 6, 7). However, long-term administration of LZD may cause severe side effects such as anemia, thrombocytopenia, and peripheral neuropathy (8). PNU-100480 (sutezolid; PNU) is an oxazolidinone analogue that has been reported to have an improved safety profile compared to LZD (2). PNU has an MIC similar to that of LZD for M. tuberculosis in vitro but has more potent bactericidal activity in ex vivo whole-blood cultures and in a murine model of TB (9-11). In mice, addition of PNU not only enhanced the bactericidal activity during the initial ph...

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of Three Oxazolidinones against Nonreplicating Mycobacterium tuberculosis

Zhang

Sala

Dhar

et al. 2014

Antimicrob Agents Chemother

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“…1). Continued exploration of the SAR of the oxazolidinone ring C-5 position has led to the discovery of alternatives to acylaminomethyl groups that maintain or enhance antibacterial potency, such as the 1,2,3-triazol-2-yl-methyl (55), pyrid-2-yl-oxymethyl, and isoxazol-3-yl-oxymethyl groups (23). Although the initial 5-hydroxymethyl oxazolidinones examined by DuPont and Pharmacia & Upjohn were significantly weaker in potency than the 5-acylaminomethyl analogs, when combined with a potent ABCD ring system, the Dong-A scientists found that 5-hydroxymethyloxazolidinones such as DA-7157 (TR-700) ( Fig.…”

mentioning

confidence: 99%

Structure-Activity Relationships of Diverse Oxazolidinones for Linezolid-Resistant Staphylococcus aureus Strains Possessing the cfr Methyltransferase Gene or Ribosomal Mutations

Locke

Finn

Hilgers

et al. 2010

Antimicrob Agents Chemother

132

108

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“…They show good antibacterial properties, hence these heterocyclic compounds are widely used in pharmaceuticals, cosmetics, pesticides, and so on [178][179][180]. Chiral 2-oxazolidinones (Evans chiral auxiliaries) have been used in a wide range of asymmetric synthesis [181][182][183][184][185].…”

Section: Synthesis Of 2-oxazolidinones/2-imidiazolidinones Via Transementioning

confidence: 99%

Carbon dioxide: a renewable feedstock for the synthesis of fine and bulk chemicals

Patil

Tambade

Jagtap

et al. 2009

Front. Chem. Eng. China

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The syntheses of carbon dioxide (CO 2 ) based industrially important chemicals have gained considerable interest in view of the sustainable chemistry and "green chemistry" concepts. In this review, recent developments in the chemical fixation of CO 2 to valuable chemicals are discussed. The synthesis of five-member cyclic carbonates via, cycloaddition of CO 2 to epoxides is one of the promising reactions replacing the existing poisonous phosgene-based synthetic route. This review focuses on the synthesis of cyclic carbonates, vinyl carbamates, and quinazoline-2,4(1H,3H)-diones via reaction of CO 2 and epoxide, amines/phenyl acetylene, 2-aminobenzinitrile and other chemicals. Direct synthesis of dimethyl carbonate, 1,3-disubstituted urea and 2-oxazolidinones/2-imidazolidinones have limitations at present because of the reaction equilibrium and chemical inertness of CO 2 . The preferred alternatives for their synthesis like transesterification of ethylene carbonate with methanol, transamination of ethylene carbonate with primary amine and transamination reaction of ethylene carbonate with diamines/β-aminoalcohols are discussed. These methodologies offer marked improvements for greener chemical fixation of CO 2 in to industrially important chemicals.

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New classes of antibacterial oxazolidinones with C-5, methylene O-Linked heterocyclic side chains

Cited by 57 publications

References 17 publications

In Vitro and In Vivo Activities of Three Oxazolidinones against Nonreplicating Mycobacterium tuberculosis

In Vitro and In Vivo Activities of Three Oxazolidinones against Nonreplicating Mycobacterium tuberculosis

Structure-Activity Relationships of Diverse Oxazolidinones for Linezolid-Resistant Staphylococcus aureus Strains Possessing the cfr Methyltransferase Gene or Ribosomal Mutations

Carbon dioxide: a renewable feedstock for the synthesis of fine and bulk chemicals

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