β-lactam/β-lactamase inhibitor combinations: an update

Tehrani, Kamaleddin Haj Mohammad Ebrahim; Martin, Nathaniel I.

doi:10.1039/c8md00342d

Cited by 125 publications

(109 citation statements)

References 173 publications

(189 reference statements)

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“…Bisthiazolidine 1a, and isobutyraldehyde 2a were selected as a model for the exchange reaction. We first assayed the reaction in MeOH, both in absence of catalyst or using additives as pTsOH ac., [20] NH 4 OAc, [21] and L-Proline, [22] (see Table 1). The results showed that a catalyst is needed for the reaction to proceed, and the best conversion was obtained when using NH 4 OAc.…”

Section: Resultsmentioning

confidence: 99%

“…We first assayed the reaction in MeOH, both in absence of catalyst or using additives as pTsOH ac., [20] NH 4 OAc, [21] and L-Proline, [22] (see Table 1). The results showed that a catalyst is needed for the reaction to proceed, and the best conversion was obtained when using NH 4 OAc. Once the best catalyst was established, the use of microwave (MW) and conventional heating was explored to perform the exchange reaction.…”

Section: Resultsmentioning

confidence: 99%

“…When the aldehyde 2a is dissolved in MeOD-d 4 , an equilibrium is established with the hemiacetal I. Upon addition of NH 4 OAc, key proton resonances corresponding to the carbinolamine II, imine III, and enamine IV could be observed at 3.84, 7.64 and 6.39 ppm, respectively. The equilibrium between compounds II and III is confirmed by the observation of an exchange peak in the 1D 1 H, 1 H-NOESY spectrum of the imine proton of compound III to the proton attached to the hemiaminal carbon in compound II (Figure 1).…”

Section: Isobutylimine Formation (Step A)mentioning

confidence: 99%

“…Bisthiazolidines ( 1 ) are enantiomerically pure bicycles previously prepared in high yields (Scheme ) . Interestingly, they display activity against Metallo‐β‐Lactamases (MBLs), a diverse set of enzymes that catalyze the hydrolysis of a broad range of β‐lactam drugs including carbapenems , . These compounds have been recently characterized as cross‐class inhibitors against seven different MBLs, some of clinical relevance like NDM‐1, VIM‐2, and L1 , …”

Section: Introductionmentioning

confidence: 99%

“…[2] Interestingly, they display activity against Metallo--Lactamases (MBLs), a diverse set of enzymes that catalyze the hydrolysis of a broad range of -lactam drugs including carbapenems. [3,4] These compounds have been recently characterized as cross-class inhibitors against seven different MBLs, some of clinical relevance like NDM-1, VIM-2, and L1. [2,[5][6][7] Bicycles 1 are obtained in a tandem reaction by double condensation of L-aminothiols with two molecules of mercaptoacetaldehyde.…”

Section: Introductionmentioning

confidence: 99%

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Preparation and Mechanistic Studies of 2‐Substituted Bisthiazolidines by Imine Exchange

et al. 2020

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Bisthiazolidines (BTZ) are bicyclic compounds considered as penicillin analogs that inhibit the full range of Metallo‐β‐Lactamases (MBLs) and potentiate β‐lactam activity against resistant bacteria. Herein, we present a new methodology to prepare 2‐substituted bisthiazolidines by aldehyde exchange. Thirteen new bisthiazolidines were prepared using this methodology, with yields ranging from 31 to 75 %. The reaction is based on in situ imines formation, which are able to exchange side chains. The reaction intermediates were studied based on NMR experiments, and a key imine 1b‐II could be detected in the reaction mixture. Furthermore, a DFT computational analysis was performed to gain insights into the reaction mechanism, allowing us to unveil the different pathways and their activation barriers within the synthetic route. The results suggest that the most favorable route involve the formation of the thiazolidine 1b‐III by i) a N‐assisted N–C bond cleavage, and ii) a thiol‐mediated 5 endo‐trig cyclization followed by a C–N bond cleavage. In contrast with previously reported evidence, the imine metathesis was discarded as a plausible pathway. Finally, the reaction of 1b‐III with aldehyde 2a leads to bicycle 4a via the iminium ion 1b‐V.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Isobutylimine Formation (Step A)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preparation and Mechanistic Studies of 2‐Substituted Bisthiazolidines by Imine Exchange

et al. 2020

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Considerations and Caveats in Combating ESKAPE Pathogens against Nosocomial Infections

et al. 2019

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ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are among the most common opportunistic pathogens in nosocomial infections. ESKAPE pathogens distinguish themselves from normal ones by developing a high level of antibiotic resistance that involves multiple mechanisms. Contemporary therapeutic strategies which are potential options in combating ESKAPE bacteria need further investigation. Herein, a broad overview of the antimicrobial research on ESKAPE pathogens over the past five years is provided with prospective clinical applications.

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β-lactam/β-lactamase inhibitor combinations: an update

Abstract: Antibiotic resistance caused by β-lactamase production continues to present a growing challenge to the efficacy of β-lactams and their role as the most important class of clinically used antibiotics.

Cited by 125 publications

References 173 publications

Preparation and Mechanistic Studies of 2‐Substituted Bisthiazolidines by Imine Exchange

Preparation and Mechanistic Studies of 2‐Substituted Bisthiazolidines by Imine Exchange

Medicinal Chemistry of β‐Lactam Antibiotics

Considerations and Caveats in Combating ESKAPE Pathogens against Nosocomial Infections

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