Synthesis of 3-Substituted-clavams: Antifungal Properties, DD-Peptidase and β-Lactamase Inhibition

Cierpucha, Maciej; Panfil, Irma; Danh, Tong Thanh; Chmielewski, Marek; Kurzątkowski, W; Rajnisz, Aleksandra; Solecka, Jolanta

doi:10.1038/ja.2007.80

Cited by 10 publications

(5 citation statements)

References 39 publications

(21 reference statements)

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“…For example, β-lactams fused to a sulfur-substituted five-membered ring (i.e., penicillin derivatives) exhibit significantly divergent antibiotic properties than when fused to an unsaturated oxygen-substituted six-membered ring (i.e., oxacephem derivatives): the aminopenicillin amoxicillin is more efficacious against Staphylococcus aureus than Pseudomonas aeruginosa, while the converse is observed for the slightly modified carboxypenicillin carbenicillin. , Current strategies to circumvent antibiotic resistance include synthesizing β-lactam antibiotics with different ring sizes and heteroatom substitution − ,, as well as preparing β-lactamase inhibitors such as the oxabicyclic clavulanic acid. ,− This avenue of research remains a high priority in light of the inevitable obsolescence of traditional antibiotics such as penicillin and amoxicillin.…”

Section: Introductionmentioning

confidence: 99%

Guidelines for β-Lactam Synthesis: Glycal Protecting Groups Dictate Stereoelectronics and [2+2] Cycloaddition Kinetics

et al. 2020

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The alkene-isocyanate cycloaddition method affords β-lactams from glycals with high regio- and stereoselectivity, but the factors that determine substrate reactivity are poorly understood. Thus, we synthesized a library of 17 electron-rich alkenes (glycals) with varied protecting groups to systematically elucidate the factors that influence their reactivity toward the electron-poor trichloroacetyl isocyanate. The experimentally determined reaction rates exponentially correlate with the computationally determined highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) gap and natural bond orbital (NBO) valence energies. The electron-withdrawing ability of the protecting groups, but not bulk, impacts the electron density of the glycal allyloxocarbenium system when oriented pseudo-axially (i.e., stereoelectronics). In this conformation, ring σC–O* orbitals oriented antiperiplanar to the allyloxocarbenium system decrease glycal reactivity via negative hyperconjugation as protecting group electron withdrawal increases. Transition-state calculations reveal that protecting group stereoelectronics direct the reaction to proceed via an asynchronous one-step mechanism through a zwitterionic species. The combined experimental and computational findings, along with experimental validation on an unknown glycal, provide insight on the reaction mechanism and the role of distant protecting groups in glycal reactivity. Together, these studies will aid in the synthesis of new β-lactam antibiotics, β-lactamase inhibitors, and bicyclic carbohydrate-β-lactam monomers prepared by the alkene-isocyanate method.

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Section: Introductionmentioning

confidence: 99%

Guidelines for β-Lactam Synthesis: Glycal Protecting Groups Dictate Stereoelectronics and [2+2] Cycloaddition Kinetics

et al. 2020

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“…Diverse biological activities of β-lactam derivatives still inspire the interest of synthetic organic chemists in synthesis of new compounds containing the azetidinone fragment in their structures [1][2][3][4][5][6][7][8][9][10][11][12][13]. e β-lactams were firstly synthesized in 1907 by H. Staudinger via [2 + 2] cycloaddition reaction of Schiff base from aniline and benzaldehyde with diphenylketene [14,15].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of New Bis(spiro-β-lactams) via Interaction of Methyl 1-Bromocycloalcanecarboxylates with Zinc and N,N′-Bis(arylmethylidene)benzidines

Kirillov

Nikiforova

Baibarodskikh

et al. 2019

Journal of Chemistry

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Interaction of the Reformatsky reagents, prepared from methyl 1-bromocyclopentane-1-carboxylate or methyl 1-bromocyclohexane-1-carboxylate, with N,N′-bis(arylmethylidene)benzidines has given rise to a set of intermediates as a result of nucleophilic addition to the C=N group of a substrate. Further intramolecular attack of the amide nitrogen atom onto the ester carbonyl group is responsible for the ring closure, which affords two series of spirocompounds: 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.4]octan-1-one) or 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.5]nonan-1-ones).

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“…These compounds, bis-2-oxazetidinyl macrocycles, are not, however, close analogues of classical β-lactams. Certain derivatives of naturally occurring descarboxy bicyclic β-lactams, the clavams, are also reported to have modest activity against a DD-peptidase . The low reactivity of classical β-lactams against HMMB1 enzymes must reflect the inability of the carboxylate to facilitate catalysis at these active sites, perhaps because of their unusual narrow active site cleft , and the probable need for allosteric activation of the site .…”

mentioning

confidence: 99%

“…Certain derivatives of naturally occurring descarboxy bicyclic β-lactams, the clavams, are also reported to have modest activity against a DD-peptidase. 20 The low reactivity of classical β-lactams against HMMB1 enzymes must reflect the inability of the carboxylate to facilitate catalysis at these active sites, perhaps because of their unusual narrow active site cleft 17,18 and the probable need for allosteric activation of the site. 21 In crystal structures of the (inert) acylenzymes generated, however, the carboxylates of classical β-lactams do appear to interact with the active site in the usual fashion.…”

mentioning

confidence: 99%

Neutral β-Lactams Inactivate High Molecular Mass Penicillin-Binding Proteins of Class B1, Including PBP2a of MRSA

Dave

Palzkill

Pratt

2013

ACS Med. Chem. Lett.

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The targets of β-lactam antibiotics are bacterial DD-peptidases (penicillin-binding proteins). β-Lactam SAR studies over many years have demonstrated the importance of a specifically placed negative charge, usually carboxylate, on these molecules. We show here that neutral analogues of classical β-lactam antibiotics are of comparable activity to the originals against β-lactam-resistant high molecular mass DDpeptidases of the B1 class, a group that includes PBP2a of methicillin-resistant Staphylococcus aureus. These neutral β-lactams may direct new development of antibiotics against certain penicillin-resistant bacteria. These molecules do have antibiotic activity against Gram-positive bacteria.

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Synthesis of 3-Substituted-clavams: Antifungal Properties, DD-Peptidase and β-Lactamase Inhibition

Cited by 10 publications

References 39 publications

Guidelines for β-Lactam Synthesis: Glycal Protecting Groups Dictate Stereoelectronics and [2+2] Cycloaddition Kinetics

Guidelines for β-Lactam Synthesis: Glycal Protecting Groups Dictate Stereoelectronics and [2+2] Cycloaddition Kinetics

Synthesis of New Bis(spiro-β-lactams) via Interaction of Methyl 1-Bromocycloalcanecarboxylates with Zinc and N,N′-Bis(arylmethylidene)benzidines

Neutral β-Lactams Inactivate High Molecular Mass Penicillin-Binding Proteins of Class B1, Including PBP2a of MRSA

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