ChemInform Abstract: Molecular Modeling of γ‐Lactam Analogues of β‐Lactam Antibacterial Agents: Synthesis and Biological Evaluation of Selected Penem and Carbapenem Analogues.

Allen, Norris E.; Boyd, Donald B.; Campbell, J. B.; Deeter, Jack B.; Elzey, Thomas K.; Foster, B. J.; Hatfield, Lowell D.; Hobbs, J. N.; Hornback, William J.; Hunden, David C.; Jones, Noel D.; Kinnick, M. D.; Morin, John M.; Munroe, John E.; Swartzendruber, John K.; Vogt, D. G.

doi:10.1002/chin.198931293

Cited by 2 publications

(2 citation statements)

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“…Recent efforts to [85], 5.2 [86], 5.3 [87], 5.4 [88], 5.5 [89], 5.6 [90], 5.7 [91] and 5.8 [92]). (B) Examples of inactive compounds (5.9 [93,94], 5.10 [93,94], 5.11 [88], 5.12 [95,96], 5.13 [97], 5.14 [98], 5.15 [99] and 5.16 [100]). …”

Section: Lactivicinmentioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

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Avibactam, which is the first non-β-lactam β-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine β-lactamase inhibitor with activity against class A, class C, and, some, class D β-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-β-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and β-lactamase inhibitors. Like the β-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, avibactam reacts reversibly with its β-lactamase targets. We discuss chemical factors that may account for the apparently special nature of β-lactams and related compounds as antibacterials and β-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-β-lactam antibacterials acting similarly to β-lactams are discussed.

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Section: Lactivicinmentioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

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“…The /3-lactam ring, which is the hallmark of the well-studied penicillin and cephalosporin classes of antibiotics,3 is replaced by a pyrazolidinone ring4'5 (Figure 1). Recent computations and chemistry have shown that the fourmembered ring could be replaced by a 7-lactam ring,6 7 while retaining at last a very low level of antibacterial activity. Introducing a second nitrogen into the fivemembered ring significantly boosted activity to a useful range.8™12 The advantages of this ring bioisostere are that it opens up a novel structural series and it could in principle afford antibacterial or pharmacokinetic properties not achievable with traditional /3-lactam antibiotics.…”

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confidence: 99%

Application of the hypersurface iterative projection method to bicyclic pyrazolidinone antibacterial agents

Boyd

1993

J. Med. Chem.

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Bicyclic pyrazolidinones are a class of synthetic antibacterial agents in which the beta-lactam ring is replaced by a five-membered ring. These compounds possess electronic and shape properties required for inhibiting penicillin-binding proteins essential for bacterial cell growth. A novel approach called the hypersurface iterative projection (HIP) method, which is based on three-dimensional computer graphics, allows available structure-activity information to be extrapolated to new synthetic targets. By updating the data set as the SAR evolves, the computer graphics reveal regions of parameter space to explore for optimum activity and regions yet unexplored. A large substituent parameter database is used to propose appropriate substituents. For the bicyclic pyrazolidinones, lipophilicity and particularly electron-withdrawing properties of the 3-substituent are shown to correlate strongly with minimum inhibitory concentrations (MIC). Antibacterial potency is intimately related to the activating effect of 3-substituents on chemical reactivity. The HIP method succeeded in proposing the most potent member of the series prior to synthesis and also showed when all of parameter space was reasonably well explored to the extent the chemistry allowed.

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ChemInform Abstract: Molecular Modeling of γ‐Lactam Analogues of β‐Lactam Antibacterial Agents: Synthesis and Biological Evaluation of Selected Penem and Carbapenem Analogues.

Abstract: From computational chemistry studies it is suggested that γ‐lactam analogues of penems and carbapenems possessing a 7β‐acylamino side‐chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics.

Cited by 2 publications

References 1 publication

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

Application of the hypersurface iterative projection method to bicyclic pyrazolidinone antibacterial agents

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