Chemistry of cephalosporin antibiotics. XIII. Deacetoxycephalosporins. Synthesis of cephalexin and some analogs

Ryan, Charles W.; Simon, Robert L.; Heyningen, E. M. Van

doi:10.1021/jm00302a026

Cited by 59 publications

(11 citation statements)

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“…Cephems , also known as cephalosporins, differ from penems by having a dihydrothiazine ring fused to the β-lactam ring ( Hughes, 2017a , b ). First generation cephems generally possess an aromatic acylamino side chain at C7 and exhibit potent Gram-positive activity ( Godzeski et al, 1963 ; Spencer et al, 1966a , b ; Ryan et al, 1969 ; Hsieh and Ho, 1975 ).…”

Section: Structural Platforms and β-Lactam Classesmentioning

confidence: 99%

The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition

Turner

Muraoka

Bedenbaugh³

et al. 2022

Front. Microbiol.

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Beta-lactam antibiotics remain one of the most commonly prescribed drug classes, but they are limited by their propensity to cause hypersensitivity reactions (e.g., from allergy to anaphylaxis) as well as by the emergence of bacteria with a myriad of resistance mechanisms such as β-lactamases. While development efforts continue to focus on overcoming resistance, there are ongoing concerns regarding cross-contamination of β-lactams during manufacturing and compounding of these drugs. Additionally, there is a need to reduce levels of drugs such as β-lactam antibiotics in waste-water to mitigate the risk of environmental exposure. To help address future development of effective remediation chemistries and processes, it is desired to better understand the structural relationship among the most common β-lactams. This study includes the creation of a class-wide structural ordering of the entire β-lactam series, including both United States Food and Drug Association (US-FDA)-approved drugs and experimental therapies. The result is a structural relational map: the “Lactamome,” which positions each substance according to architecture and chemical end-group. We utilized a novel method to compare the structural relationships of β-lactam antibiotics among the radial cladogram and describe the positioning with respect to efficacy, resistance to hydrolysis, reported hypersensitivity, and Woodward height. The resulting classification scheme may help with the development of broad-spectrum treatments that reduce the risk of occupational exposure and negative environmental impacts, assist practitioners with avoiding adverse patient reactions, and help direct future drug research.

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Section: Structural Platforms and β-Lactam Classesmentioning

confidence: 99%

The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition

Turner

Muraoka

Bedenbaugh³

et al. 2022

Front. Microbiol.

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“…It appears that the high antibacterial activity of cefotiam depends mainly on the aminothiazole acyl side chain at the 7-position of the cephalosporin (9). Introduction of various substituents into the a-carbon of the acyl side chain at the 7-position of the cephalosporin resulted in cephalosporins with various properties (1,14,20 10 days in the case of K. pneumoniae infection; it was started at 3 days after infection and continued for 5 days in the case of P. mirabilis infection. The number of bacteria in the lung, bladder wall, kidney, and urine was determined by the method previously described (5, 7).…”

mentioning

confidence: 99%

Cefmenoxime (SCE-1365), a novel broad-spectrum cephalosporin: in vitro and in vivo antibacterial activities

Tsuchiya¹,

Kondo²,

Kida³

et al. 1981

Antimicrob Agents Chemother

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The activity of cefmenoxime (SCE-1365), 7,8-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid, was compared with that of other cephalosporins. Cefinenoxime exhibited high activity against a wide variety of gram-positive and gramnegative bacteria. The in vitro activity of cefmenoxime against Streptococcus pyogenes, Haemophilus influenzae, and Enterobacteriaceae, including indolepositive Proteus, Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii, was 10 to 1,000 times greater than that of several other cephalosporins. Against Pseudomonas aeruginosa, cefmenoxime showed activity two to four times that of sulbenicillin and carbenicillin but less than that of cefsulodin. Variation in pH, addition of horse serum, and type of growth medium had definite effects on the activity of cefmenoxime, and the inoculum size affected the activity against bacterial species. In Escherichia coli cefmenoxime showed marked affinity for penicillin-binding protein 3 (PBP-3), followed by PBP-1 (1A and 1B). This affinity profile was well correlated with its filamentous cell-forming activity under extremely low drug concentrations and with its bactericidal activity against microorganisms. The high in vitro activity of cefmenoxime was reflected in the degree of protection observed in mice infected intraperitoneally with a wide variety of gram-positive and gram-negative bacteria. Furthermore, cefmenoxime showed good therapeutic activity against infection models in mice such as respiratory tract infection caused by Klebsiellapneumoniae and urinary tract infection caused by Proteus mirabilis.In recent years, with the increasing use of cephalosporins, an increasing number of infections caused by cephalosporin-resistant bacteria have been observed. The present report concerns the activity of cefmenoxime (SCE-1365),

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“…This enabled the company to succeed in developing the well-reputed cephalosporin, cefamandole (Wick et al 1972). Similarly, introduction of a D-phenylglycin moiety into the cephalosporin structure led to an orally active cephalosporin (Ryan al. 1969).…”

Section: Sce-1365mentioning

confidence: 99%

An approach to broad-spectrum cephalosporins

Morita

Nomura

Numata

et al. 1980

Phil. Trans. R. Soc. Lond. B

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Based on our view that cephalosporins with potent activities share active hydrogen(s) on the alpha-carbon of the side chain acyl, we undertook to introduce beta-ketoacid moieties onto the cephalosporin structure. Thus, starting with deacetylcephalosporin C (DCPC), first made available in quantities by our own fermentation technique, 7-amino-3'-O-acetoacetyldeacetylcephalosporanic acid (7-AACA) was made accesible. Acylation of 7-AACA with various beta-ketoacids followed by substitution at the 3'-position led to 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-3-[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl]ceph-3-em-4-carboxylic acid (SCE-963, cefotiam), a potent broad-spectrum cephalosporin. Further elaboration of the structure of cefotiam led to an extended broad-spectrum cephalosporin, SCE-1365. These two classes of cephalosporins, together with our previously reported antipseudomonal cephalosporin (SCE-129, cefsulodin), could control a wide range of pathogenic bacteria.

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Chemistry of cephalosporin antibiotics. XIII. Deacetoxycephalosporins. Synthesis of cephalexin and some analogs

Cited by 59 publications

References 0 publications

The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition

The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition

Cefmenoxime (SCE-1365), a novel broad-spectrum cephalosporin: in vitro and in vivo antibacterial activities

An approach to broad-spectrum cephalosporins

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