The chemical reactivity of penicillins and other β-lactam antibiotics

Proctor, Philip; Gensmantel, Nigel P.; Page, Michael I.

doi:10.1039/p29820001185

Cited by 85 publications

(94 citation statements)

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“…The generated b-lactam antibiotic itself eventually decomposes to ring-opened compounds (k d ). Page's team 11 found that, for benzylpenicillin methyl ester, the sum k p +k np was sixteen times larger than k d . The rate constant k p being small in this case, this means that k np equalled 16 k d .…”

Section: Resultsmentioning

confidence: 99%

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Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation

Paternotte

Fan

Scrève

et al. 2001

Bioorganic & Medicinal Chemistry

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AbstractÐReadily hydrolysable basic and dibasic esters of ampicillin were synthesised by alkylation of the carboxylate function of ampicillin to obtain prodrugs that may accumulate in cells and allow for an intracellular delivery of ampicillin (Fan et al., Bioorg. Med. Chem. Lett. 1997, 7, 3107). We found that the b-lactam ring cleavage and the hydrolysis of the ester function were competitive reactions. The prerequisite for biological activity of compounds of this type is therefore that ester hydrolysis proceeds faster than ring opening. Some synthesised compounds show promise as prodrugs since they displayed a reasonable stability and regenerate large quantities of bioactive ampicillin in broth. #

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Section: Resultsmentioning

confidence: 99%

“…7,12 This electronwithdrawing e ect is re¯ected in the shift of the amine pK a from 5.2 for benzylpenicilloic acid to 3.2 for its methyl ester. 11 Useful esters of b-lactam antibiotics have thus to feature the following kinetic characteristics:…”

Section: Resultsmentioning

confidence: 99%

Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation

Paternotte

Fan

Scrève

et al. 2001

Bioorganic & Medicinal Chemistry

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“…These results are comparable to those reported for the alkaline hydrolysis of the vinylogous cephalosporins containing a potential leaving group at C-3' (4, n = 0), for which a β lg value close to zero was also determined. 41 In contrast, log k OH -values correlate with σ I values for the substituents at C-4, including those that are not expelled, yielding Hammett ρ I values of 2.8 and 3.4 for the series 5a-d and 5e-j, respectively ( Figure 4). These ρ I values are consistent with rate-limiting attack of hydroxide on the β-lactam carbonyl atom and indicate that the effect exerted by C-4 substituents on the alkaline hydrolysis of 5 is purely inductive.…”

Section: Alkaline Hydrolysismentioning

confidence: 96%

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

et al. 2007

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“…No significant spontaneous hydrolysis is observed in the pH-rate profile for the hydrolysis of penicillins, but the b-lactam moiety does undergo an acid-catalyzed degradation. By contrast, the hydrolysis of cephalosporins shows a spontaneous pHindependent hydrolysis and is less reactive by a factor of about 10 4 towards acid than are penicillins [206]. Penicillins undergo an acid-and a base-catalyzed hydrolysis, but there is no significant uncatalyzed reaction, the pH minimum being around 7 for spontaneous or water-induced degradation.…”

Section: Hydrolysismentioning

confidence: 95%

The Chemistry of 2‐Azetidinones (β‐Lactams)

Alcaide¹,

Almendros²,

Luna³

2011

Modern Heterocyclic Chemistry

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The large number of recent reports on b-lactam chemistry demonstrates the increasing interest in this important class of compounds. Monocyclic b-lactams frequently serve as precursors for the synthesis of classical bicyclic b-lactam antibiotics. The cyclic 2-azetidinone skeleton has been extensively used as a template on which to build the heterocyclic structure fused to the four-membered ring, using the chirality and functionalization of the b-lactam nucleus as a stereocontrolling element. The discovery of nonclassical b-lactam antibiotics, such as monobactams and nocardicins, coupled with ever-growing new applications such as enzyme inhibition has triggered a renewed interest in the building of new monocyclic b-lactam derivatives. Besides the utility of b-lactams as biologically active agents, they are used as intermediates in a-and b-amino acid synthesis, as well as building blocks for alkaloids, heterocycles, taxoids and other types of compounds of biological and medicinal interest. Physicochemical Data Computational ChemistryTheoretical studies show that b-lactams are weaker bases, in the gas phase, than acyclic amides [1]. The attenuation of basicity upon cyclization is stronger than that found for cyclic ketones of similar size due to the existence of a negative hyperconjugation effect that is present in b-lactams but not in cyclic ketones. Ab initio calculations indicate that both b-lactams and acyclic amides are oxygen bases, but the gap between the oxygen and nitrogen intrinsic basicities is much smaller in the former due to the aforementioned cyclization effects. This decrease of the oxygen Modern Heterocyclic Chemistry, First Edition. Edited

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The chemical reactivity of penicillins and other β-lactam antibiotics

Cited by 85 publications

References 0 publications

Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation

Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

The Chemistry of 2‐Azetidinones (β‐Lactams)

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