Synthesis and <i>in vitro</i> activity of the penem antibiotics

McCombie, Stuart W.; Ganguly, Ashit K.

doi:10.1002/med.2610080304

Cited by 29 publications

(2 citation statements)

References 61 publications

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“…A number of methods for construction of carba- and thiopenems have been reported in the synthetic chemistry literature. − Key strategies include C–C, ,,− C–N, and C–S − bond formation for preparation of the five-membered ring. However, many of the methods that have proven successful for carbapenems are not applicable to thiopenems.…”

Section: Resultsmentioning

confidence: 99%

“…Penems, a class of β-lactam antibiotics, have been the subject of intense research over the last three decades. − Sulopenem ( 1 ) is a novel 2-thioalkyl penem that was in development for a broad range of indications (Figure ). , In order to support this research program, a practical process for the large-scale preparation of this antibacterial was required.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Practical and Convergent Process for the Preparation of Sulopenem

Brenek

Caron

Chisowa

et al. 2012

Org. Process Res. Dev.

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Previous synthetic processes for the preparation of sulopenem involved multistep linear sequences in which the chiral sulfoxide side chain was introduced early in the process. This contribution summarizes the development of a practical and convergent process for the large-scale preparation of 1. The key step in the synthesis involves cyclization of an oxalimide intermediate to provide the thiopenem core. This convergent strategy allows for late introduction of the expensive and labile chiral sulfoxide subunit. Additionally, a regioselective sulfur oxidation and an improved deprotection sequence were developed. The latter provides API of high purity without the need for recrystallization.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of a Practical and Convergent Process for the Preparation of Sulopenem

Brenek

Caron

Chisowa

et al. 2012

Org. Process Res. Dev.

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β‐Lactamase Inhibitors

Stam

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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The antibacterial effectiveness of penicillins, cephalosporins, and other β‐lactam antibiotics depends on the inactivation of transpeptidases involved in bacterial cell wall synthesis. Bacteria that are resistant to β‐lactam antibiotics often produce enzymes called β‐lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the β‐lactam ring to give products devoid of antibacterial activity. One approach to combating antibiotic resistance caused by β‐lactamase is to inhibit the enzyme. Effective combinations of enzyme inhibitors with β‐lactam antibiotics such as penicillins or cephalosporins result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. The most important β‐lactamases to inhibit clinically are the gram‐positive penases, the gram‐negative TEM, which are Richmond‐Sykes type III, and the gram‐negative chromosomal cephalosporinases–cephases which are Richmond‐Sykes type I. These enzymes may be referred to as penase, TEM(III), and cephase(I). These clinically important β‐lactamases are serine proteases that form an acyl enzyme intermediate with β‐lactam substrates and β‐lactam‐derived β‐lactamase inhibitors. A number of β‐lactamase‐resistant penicillins and cephalosporins were found to be β‐lactamase inhibitors. No clinically useful inhibitors have been identified from this class. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important β‐lactamases, including penases and Richmond‐Sykes types II, III, IV, V, VI ( Bacteroides ). Carbapenems are another class of natural product β‐lactamase inhibitors. Many penem β‐lactamase inhibitors are potent antibacterials. Penicillanic acid sulfone, (2( S )‐ cis )‐3,3‐dimethyl‐7‐oxo‐4,4‐dioxide‐4‐thia‐1‐azabicyclo [3.2.0]heptane‐2‐carboxylic acid (sulbactam) ( , ), C 8 H 11 NO 5 S, is a weak antibacterial, but is a potent irreversible inactivator of many β‐lactamases, including penases and Richmond‐Sykes type II, III, IV, V, and VI ( Bacteroides ) β‐lactamases. Sulbactam is better than clavulanic acid against type I cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sulfones have been reported to be β‐lactamase inhibitors. Among penam β‐lactamase inhibitors, of 6‐β‐bromopenicillanic acid, a potent inhibitor, has progressed to clinical trials. Although a broad range of β‐lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid manufactured by SmithKline Beecham is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin, C 15 H 16 N 2 O 6 S, has the trade name, Timentin. The oral version of sulbactam in combination with ampicillin, produced by Pfizer is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any β‐lactam antibiotic as Betamaze.

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Penems: A New Generation of β‐Laetam Antibiotics

Sedelmeier¹

1995

Organic Synthesis Highlights II

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Synthesis and in vitro activity of the penem antibiotics

Cited by 29 publications

References 61 publications

Development of a Practical and Convergent Process for the Preparation of Sulopenem

Development of a Practical and Convergent Process for the Preparation of Sulopenem

β‐Lactamase Inhibitors

Penems: A New Generation of β‐Laetam Antibiotics

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