Thiazolidine ring opening in penicillin derivatives. Part 2. Enamine formation

Davis, Andrew M.; Layland, Nicola J.; Page, Michael I.; MARTIN, F.; O'Ferrall, Rory More

doi:10.1039/p29910001225

Cited by 14 publications

(7 citation statements)

References 1 publication

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“…A small amount of epimerization may occur at C5 during preparation of the model esters used here but this will not affect the IR absorbance frequency of the ester carbonyl. Epimerization at C6 is too slow to have occurred in our procedures [23][24][25].…”

Section: The Strength Of the Hydrogen Bondsmentioning

confidence: 94%

Hydrogen bonding and protein perturbation in β-lactam acyl-enzymes of Streptococcus pneumoniae penicillin-binding protein PBP2x

et al. 1999

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A soluble form of Streptococcus pneumoniae PBP2x, a molecular target of penicillin and cephalosporin antibiotics, has been expressed and purified. IR difference spectra of PBP2x acylated with benzylpenicillin, cloxacillin, cephalothin and ceftriaxone have been measured. The difference spectra show two main features. The ester carbonyl vibration of the acyl-enzyme is ascribed to a small band between 1710 and 1720 cm-1, whereas a much larger band at approx. 1640 cm-1 is ascribed to a perturbation in the structure of the enzyme, which occurs on acylation. The protein perturbation has been interpreted as occurring in beta-sheet. The acyl-enzyme formed with benzylpenicillin shows the lowest ester carbonyl vibration frequency, which is interpreted to mean that the carbonyl oxygen is the most strongly hydrogen-bonded in the oxyanion hole of the antibiotics studied. The semi-synthetic penicillin cloxacillin is apparently less well organized in the active site and shows two partially overlapping ester carbonyl bands. The penicillin acyl-enzyme has been shown to deacylate more slowly than that formed with cloxacillin. This demonstrates that the natural benzylpenicillin forms a more optimized and better-bonded acyl-enzyme and that this in turn leads to the stabilization of the acyl-enzyme required for effective action in the inhibition of PBP2x. The energetics of hydrogen bonding in the several acyl-enzymes is discussed and comparison is made with carbonyl absorption frequencies of model ethyl esters in a range of organic solvents. A comparison of hydrolytic deacylation with hydroxaminolysis for both chymotryspin and PBP2x leads to the conclusion that deacylation is uncatalysed.

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Section: The Strength Of the Hydrogen Bondsmentioning

confidence: 94%

Hydrogen bonding and protein perturbation in β-lactam acyl-enzymes of Streptococcus pneumoniae penicillin-binding protein PBP2x

et al. 1999

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“…The prefix seco (Latin verb secare) is used in antibiotics nomenclature [55], and it means to cut. Two penicilloic acids of penicillin G and amoxicillin are already well known in the literature [56][57][58], and some of their stable amides-products of the amino-and ammonolysis of β-lactam ring of parent antibiotics-have also already been described [59][60][61].…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Antibacterial Activity of Ionic Liquids and Organic Salts Based on Penicillin G and Amoxicillin hydrolysate Derivatives against Resistant Bacteria

et al. 2020

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The preparation and characterization of ionic liquids and organic salts (OSILs) that contain anionic penicillin G [secoPen] and amoxicillin [seco-Amx] hydrolysate derivatives and their in vitro antibacterial activity against sensitive and resistant Escherichia coli and Staphylococcus aureus strains is reported. Eleven hydrolyzed β-lactam-OSILs were obtained after precipitation in moderate-to-high yields via the neutralization of the basic ammonia buffer of antibiotics with different cation hydroxide salts. The obtained minimum inhibitory concentration (MIC) data of the prepared compounds showed a relative decrease of the inhibitory concentrations (RDIC) in the order of 100 in the case of [C2OHMIM][seco-Pen] against sensitive S. aureus ATCC25923 and, most strikingly, higher than 1000 with [C16Pyr][seco-Amx] against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. These outstanding in vitro results showcase that a straightforward transformation of standard antibiotics into hydrolyzed organic salts can dramatically change the pharmaceutical activity of a drug, including giving rise to potent formulations of antibiotics against deadly bacteria strains.

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“…29 reported an estimated second-order kinetic constant of 6 X 103 mol-1 s-l (30 "C) for epimerization catalyzed by hydroxyl ions at C (6). Such a value corresponds to a pseudo-first-order constant roughly 25 times smaller than that obtained by us at pH 10.5.…”

Section: Discussionmentioning

confidence: 67%