The synthesis and SAR of rhodanines as novel class C β-lactamase inhibitors

Grant, Eugene B.; Guiadeen, Deodialsingh; Baum, Ellen Z.; Foleno, Barbara D.; Hu, Jin; Montenegro, Deborah A.; Nelson, Erin A; Bush, Karen; Hlasta, Dennis J.

doi:10.1016/s0960-894x(00)00444-3

Cited by 128 publications

(66 citation statements)

References 8 publications

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“…Although class A ␤-lactamases can be inactivated by clavulanic acid, sulbactam, and tazobactam, no efficient inhibitors of the members of the three other classes (classes B, C, and D) are available. Recently, the inhibition of class C ␤-lactamases by rhodanines similar to those used in this study has been described (19). In the present work, we have shown that several non-␤-lactam compounds, arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones ( Fig.…”

supporting

confidence: 61%

Interactions between Penicillin-Binding Proteins (PBPs) and Two Novel Classes of PBP Inhibitors, Arylalkylidene Rhodanines and Arylalkylidene Iminothiazolidin-4-ones

Zervosen

Lu²,

Chen

et al. 2004

Antimicrob Agents Chemother

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Several non-␤-lactam compounds were active against various gram-positive and gram-negative bacterial strains. The MICs of arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones were lower than those of ampicillin and cefotaxime for methicillin-resistant Staphylococcus aureus MI339 and vancomycinresistant Enterococcus faecium EF12. Several compounds were found to inhibit the cell wall synthesis of S. aureus and the last two steps of peptidoglycan biosynthesis catalyzed by ether-treated cells of Escherichia coli or cell wall membrane preparations of Bacillus megaterium. The effects of the arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-one derivatives on E. coli PBP 3 and PBP 5, Streptococcus pneumoniae PBP 2xS (PBP 2x from a penicillin-sensitive strain) and PBP 2xR (PBP 2x from a penicillin-resistant strain), low-affinity PBP 2a of S. aureus, and the Actinomadura sp. strain R39 and Streptomyces sp. strain R61 DDpeptidases were studied. Some of the compounds exhibited inhibitory activities in the 10 to 100 M concentration range. The inhibition of PBP 2xS by several of them appeared to be noncompetitive. The dissociation constant for the best inhibitor (K i ‫؍‬ 10 M) was not influenced by the presence of the substrate.

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supporting

confidence: 61%

Interactions between Penicillin-Binding Proteins (PBPs) and Two Novel Classes of PBP Inhibitors, Arylalkylidene Rhodanines and Arylalkylidene Iminothiazolidin-4-ones

Zervosen

Lu²,

Chen

et al. 2004

Antimicrob Agents Chemother

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“…First, several groups have reported compounds similar in structure to 1 as leads for unrelated biological targets (25)(26)(27)(28)(29)(30)(31). Our data suggest that some or all of these results may be attributable to the type of mechanism outlined herein, and indicate that caution should be taken when compounds containing an N-alkyl 5-arylalkylidene-2-thioxo-1,3-thiazolidin-4-one structural motif are obtained as chemical lead structures.…”

Section: Figmentioning

confidence: 99%

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-α

Carter

Scherle

Muckelbauer

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

125

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The binding of tumor necrosis factor alpha (TNF-α) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N -alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein–protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-α to TNFRc1 (IC 50 = 50 nM) and also blocked TNF-stimulated phosphorylation of Iκ-B in Ramos cells (IC 50 = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 μM. Detailed evaluation of this and related molecules revealed that compounds in this class are “photochemically enhanced” inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity ( ca. 40–100 μM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-α to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-α–TNFRc1 interaction.

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“…The anti-microbial activity of rhodanines has been known for over 50 years, and numerous studies have been reported involving the design and synthesis of anti-bacterial agents based on this heterocycle [36][37][38][39]. Furthermore, there has been a recent increase in the number of reports concerning the anti-bacterial activities of N-carboxymethyl rhodanines (Figure 1).…”

Section: Antibacterial Activity Of N-carboxymethyl Rhodaninesmentioning

confidence: 99%

The Synthesis and Anti-Bacterial Activities of N-carboxymethyl Rhodanines

Piao¹

2014

Med chem

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A large number of reports have been published in recent years regarding the use of N-carboxymethyl rhodanines as antimicrobial agents. Molecules belonging to this structural class have been reported to exhibit good inhibitory activities towards various Gram-positive bacteria, including several multidrug-resistant strains such as methicillinresistant Staphylococcus aureus and quinolone-resistant Staphylococcus aureus. In this mini-review, we have provided a summary of recent research directed towards the synthesis of N-carboxymethyl rhodanines, and their pharmacological evaluation as antimicrobial agents.

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The synthesis and SAR of rhodanines as novel class C β-lactamase inhibitors

Cited by 128 publications

References 8 publications

Interactions between Penicillin-Binding Proteins (PBPs) and Two Novel Classes of PBP Inhibitors, Arylalkylidene Rhodanines and Arylalkylidene Iminothiazolidin-4-ones

Interactions between Penicillin-Binding Proteins (PBPs) and Two Novel Classes of PBP Inhibitors, Arylalkylidene Rhodanines and Arylalkylidene Iminothiazolidin-4-ones

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-α

The Synthesis and Anti-Bacterial Activities of N-carboxymethyl Rhodanines

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