6-(Substituted methylene)penems, potent broad spectrum inhibitors of bacterial .BETA.-lactamase. I. Racemic 6-ethylidenepenems.

Basker, Michael J.; Osborne, Neal F.

doi:10.7164/antibiotics.43.70

“…Both the (Z)-(92, R = CH 3 ) [81463- and the (E)-(93, R = CH 3 ) [81463- isomers of the 6-ethyl-idenepenem sodium salt showed potent broad spectrum β-lactamase inhibitory properties and were capable of reducing the minimum inhibitory concentration (MIC) values of sensitive β-lactams, eg, Amoxycillin, when used in combination (133). Unlike the saturated counterparts, the 6methylenepenems were tolerant to profound changes at C-8.…”

Section: Biological Propertiesmentioning

confidence: 99%

Carbapenems and Penems

Southgate

¹

,

Osborne

²

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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In the period up to 1970 most β‐lactam research was concerned with the penicillin and cephalosporin group of antibiotics. Since that time, however, a wide variety of new mono‐ and bicyclic β‐lactam structures have been described. The carbapenems originated from natural sources; the penem ring and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are: 7‐oxo‐( R )‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 7 H 7 NO 3 , and 7‐oxo‐( R )‐4‐thia‐1‐azabicyclo[3.2.0]hept‐2‐ene‐2‐carboxylic acid, C 6 H 5 NO 3 S, respectively. Carbapenems include thienamycin (C 11 H 16 N 2 O 4 S), MM 4550 (C 13 H 16 N 2 O 9 S 2 ), MM 13902 (C 13 H 16 N 2 O 8 S 2 ), MM 17880 (C 13 H 18 N 2 O 2 S 2 ), PS‐5 (C 13 H 18 N 2 O 4 S), carpetimycin A (C 14 H 18 N 2 O 6 S), asparenomycin A (C 14 H 16 N 2 O 6 S), and pluracidomycin A (C 9 H 11 NO 10 S 2 ). Only S. cattleya and S. penemfaciens have been reported to give thienamycin. Thienamycin is isolated as a colorless, hygroscopic, zwitterionic solid. Carbapenems are extremely sensitive to many reaction conditions. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin have been prepared primarily to study structure–activity relationships. One consequence of the discovery of the carbapenem natural products has been the development of new synthetic methods. Only chemical synthesis could provide the quantities of N ‐formimidoyl thienamycin (MK 0787) necessary for clinical trials and commercial production. A synthetic approach that involves the [3,4] bond formation using a carbene insertion reaction has been highly successful. A second method makes use of the lactone from acetone dicarboxylate. Thienamycin, the olivanic acids, and the majority of carbapenems are highly active broad‐spectrum antibiotics. Of the natural products, thienamycin is the most potent. Unlike carbapenems, no penems have been found in nature. The penem acid was shown to possess antibacterial activity in spite of its rather limited stability. Penems include SCH 29482 (C 10 H 13 NO 4 S 2 ), SCH 34343 (C 11 H 14 N 2 O 6 S 2 ), FCE 221201 (C 10 H 12 N 2 O 6 S), and others. 6‐Unsubstituted penems exhibit good activity against both gram‐positive and gram‐negative bacteria. Extensive carbapenem and penem antibiotic research has been ongoing since thienamycin was discovered in 1978. However, only the imipenem–cilastatin combination has become a commercial product. Meropenem was expected to be the second carbapenem on the market.

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“…4.0]undec-7-ene (DBU)at low temperature resulted in the smooth loss of acetic acid and excellent yields of the Z-isomers (4a~4d) were obtained together with small amounts of the £-isomers (5a~5d). The isomers were readily separable by column chromatography.…”

Section: Chemistrymentioning

confidence: 99%

“…JAN. 1990 Compound IRvmax (CHC13) UV A^a°xHnm was evaporated and chromatographed eluting with dichloromethane -EtOAc mixtures to give the Z-isomer (4). In some cases a small amount of the less polar jE-isomer (5) was obtained.…”

Section: Penem Esters (4 and 5): General Elimination Proceduresmentioning

confidence: 99%

6-(Substituted methylene)penems, potent broad spectrum inhibitors of bacterial .BETA.-lactamase. II. Racemic furyl and thienyl derivatives.

Broom

¹

,

Coleman

²

,

Hunter

³

et al. 1990

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A series of racemic 6-(substituted methylene)penems have been prepared. These compounds contain a 5-memberedmonoheteroaromatic ring at C-8. The antibacterial/synergistic and /Mactamase inhibitory activities of both E-and Z-isomers and 2-substituted derivatives are compared.In our previous paper we described the synthesis and biological activity of 6-ethylidenepenems (1)1}. These novel penemderivatives are potent broad-spectrum /Mactamase inhibitors and also act as synergists with penicillins and cephalosporins against /Mactamase producing bacteria. We have investigated the replacement of the C-8 methyl group with other functions and in this paper we wish to report on the extension of this work to 6-(substituted methylene)penems (2) containing a 5-membered monoheteroaromatic moiety at C-82). ChemistryReaction of the 2-unsubstituted penem acetates (3a~3d)2) with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU)at low temperature resulted in the smooth loss of acetic acid and excellent yields of the Z-isomers (4a~4d) were obtained together with small amounts of the £-isomers (5a~5d). The isomers were readily separable by column chromatography.Substituents linked to the 2 position via carbon or sulfur were also prepared. For example in the 2-furyl series, the 2-ethylthio penem (3e)2) proved to be a versatile intermediate as it could be transformed into other 2-thio derivatives by way of the "sulfoxide displacement process"3'4*. Thus, oxidation to the sulfoxide (3f) followed by reaction with a thiol provided the 2-alkylthio penems (3g and 3h). The Z-isomers (4e, 4g and 4h) were obtained from the corresponding acetates on treatment with DBU. In the 3-furyl series, the 2-hydroxymethyl derivative (3j)2) was converted to the Z alcohol (4j) on base treatment. Further chemical modification ofhydroxyl group led to the synthesis of the penems (4k~4m).The /7-nitrobenzyl (PNB) protecting group of the Z-and^-isomers (4 and 5) was removed by hydrogenolysis over palladium on carbon followed by treatment with sodium hydrogencarbonate. The resulting sodium salts (6 and 7) were obtained as homogeneous freeze-dried solids after chromatography on Biogel P2. BiologyThe /Mactamase inhibitory activity against cell-free enzyme preparations and the synergistic effects with amoxycillin or cephaloridine against whole cells are given in Table 1. The £-isomers (7a~7d) had poorer inhibitory activity than the equivalent Z-isomers (6a~6d) against

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β‐Lactamase Inhibitors

Stam

¹

2000

Kirk-Othmer Encyclopedia of Chemical Technology

0

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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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6-(Substituted methylene)penems, potent broad spectrum inhibitors of bacterial .BETA.-lactamase. I. Racemic 6-ethylidenepenems.

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Carbapenems and Penems

Carbapenems and Penems

6-(Substituted methylene)penems, potent broad spectrum inhibitors of bacterial .BETA.-lactamase. II. Racemic furyl and thienyl derivatives.

β‐Lactamase Inhibitors

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