Dual Inhibitor of MurD and MurE Ligases from <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>

Tomašič, Tihomir; Šink, Roman; Zidar, Nace; Fic, Anja; Contreras‐Martel, Carlos; Dessen, Andréa; Patin, Delphine; Blanot, Didier; Müller-Premru, Manica; Gobec, Stanislav; Zega, Anamarija; Kikelj, D.; Mašič, Lucija Peterlin

doi:10.1021/ml300047h

Cited by 47 publications

(22 citation statements)

References 29 publications

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“…[27,32e38] have been used as oxo compounds. Acetic acid or its anhydride and sodium acetate; ethanol and ammonium acetate or piperidine [39]; toluene and ammonia acetate [33,40,41]; isopropanol and potassium tert-butylate [42,43]; toluene and L-proline [44]; dimethylformamide and sodium acetate; ethanol and monoethanolamine as well as the solid carriers and phasetransfer catalysts etc. [45,46] have been widely used as the medium and catalysts in this reaction.…”

Section: Modification Of the C5 Position Of The Thiazolidinone Corementioning

confidence: 99%

5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

Kaminskyy

Kryshchyshyn

Lesyk

2017

European Journal of Medicinal Chemistry

144

133

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The presented review is an attempt to summarize a huge volume of data on 5-ene-4-thiazolidinones being a widely studied class of small molecules used in modern organic and medicinal chemistry. The manuscript covers approaches to the synthesis of 5-ene-4-thiazolidinone derivatives: modification of the C5 position of the basic core; synthesis of the target compounds in the one-pot or multistage reactions or transformation of other related heterocycles. The most prominent pharmacological profiles of 5-ene derivatives of different 4-thiazolidinone subtypes belonging to hit-, lead-compounds, drug-candidates and drugs as well as the most studied targets have been discussed. Currently target compounds (especially 5-en-rhodanines) are assigned as frequent hitters or pan-assay interference compounds (PAINS) within high-throughput screening campaigns. Nevertheless, the crucial impact of the presence/nature of C5 substituent (namely 5-ene) on the pharmacological effects of 5-ene-4-thiazolidinones was confirmed by the numerous listed findings from the original articles. The main directions for active 5-ene-4-thiazolidinones optimization have been shown: i) complication of the fragment in the C5 position; ii) introduction of the substituents in the N3 position (especially fragments with carboxylic group or its derivatives); iii) annealing in complex heterocyclic systems; iv) combination with other pharmacologically attractive fragments within hybrid pharmacophore approach. Moreover, the utilization of 5-ene-4-thiazolidinones in the synthesis of complex compounds with potent pharmacological application is described. The chemical transformations cover mainly the reactions which involve the exocyclic double bond in C5 position of the main core and correspond to the abovementioned direction of the 5-ene-4-thiazolidinone modification.

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Section: Modification Of the C5 Position Of The Thiazolidinone Corementioning

confidence: 99%

5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

Kaminskyy

Kryshchyshyn

Lesyk

2017

European Journal of Medicinal Chemistry

144

133

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“…55 Importantly, these targets are related to different metabolic functions in bacteria, namely cell wall (UPPS) and RNA synthesis (RNAP), which have not been exploited by current antibacterial agents. By contrast, previously reported multiple targeting antibacterials with novel MOAs have been related only to single metabolic functions (e.g., platencin for fatty acid biosynthesis (FabF and FabH)56 and thiazolidin‐4‐one‐based inhibitor for peptidoglycan biosynthesis (MurD and MurE ligases57)). Moreover, the depolarisation selectivity for bacterial membranes is important, especially since this activity is known to be targeted by some natural products (e.g., telavancin58 and ceragenin59) and has been highlighted as being underdeveloped58 and may provide opportunities for further development, especially in the treatment of slow growing organisms 60.…”

Section: Discussionmentioning

confidence: 93%

A Detailed Study of Antibacterial 3‐Acyltetramic Acids and 3‐Acylpiperidine‐2,4‐diones

Jeong

Bikádi²,

Hazai³

et al. 2014

ChemMedChem

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Inspired by the core fragment of antibacterial natural products such as streptolydigin, 3-acyltetramic acids and 3-acylpiperidine-2,4-diones have been synthesised from the core heterocycle by direct acylation with the substituted carboxylic acids using a strategy which permits ready access to a structurally diverse compound library. The antibacterial activity of these systems has been established against a panel of Gram-positive and Gram-negative bacteria, with activity mostly against the former, which in some cases is very potent. Data consistent with modes of action against undecaprenylpyrophosphate synthase (UPPS) and/or RNA polymerase (RNAP) for a small subset of the library has been obtained. The most active compounds have been shown to exhibit binding at known binding sites of streptolydigin and myxopyronin at UPPS and RNAP. These systems offer potential for their antibacterial activity, and further demonstrate the use of natural products as biologically validated starting points for drug discovery.

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“…A highlight in the development of 4-thiazolidinone inhibitors was the determination of their binding mode by solving several X-ray structures of MurD/inhibitor complexes (90)(91)(92)(93). The binding modes of these compounds are very similar, as can be seen from the structures of complexes with typical inhibitors 16 and 21 (Figure 3).…”

Section: Murd Inhibitorsmentioning

confidence: 99%

“…This compound turned out to be a dual MurD and MurE inhibitor. It was endowed with antibacterial activity against S. aureus and its methicillin-resistant strain (MRSA) (MIC, 8 μg/ml) (93).…”

Section: Murd Inhibitorsmentioning

confidence: 99%

“…The γ-carboxyl group interacts with Ser415, Leu416 and Phe422, while the α-carboxyl group is held in position through interactions with Thr321 and Lys348 directly. In the MurD/21 complex (PDB entry: 2Y1O), the α-carboxyl group interacts with Lys115 and Lys348 via water molecules ( Figure 3B), which is a unique property of the binding mode of inhibitor 21 (93). No polar contacts between the protein and the central linker part of the inhibitors exist.…”

Section: Murd Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

MurD enzymes: some recent developments

Šink

Barreteau

Patin

et al. 2013

BioMolecular Concepts

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The synthesis of the peptide stem of bacterial peptidoglycan involves four enzymes, the Mur ligases (MurC, D, E and F). Among them, MurD is responsible for the ATP-dependent addition of d-glutamic acid to UDP-MurNAc-l-Ala, a reaction which involves acyl-phosphate and tetrahedral intermediates. Like most enzymes of peptidoglycan biosynthesis, MurD constitutes an attractive target for the design and synthesis of new antibacterial agents. Escherichia coli MurD has been the first Mur ligase for which the tridimensional (3D) structure was solved. Thereafter, several co-crystal structures with different ligands or inhibitors were released. In the present review, we will deal with work performed on substrate specificity, reaction mechanism and 3D structure of E. coli MurD. Then, a part of the review will be devoted to recent work on MurD orthologs from species other than E. coli and to cellular organization of Mur ligases and in vivo regulation of the MurD activity. Finally, we will review the different classes of MurD inhibitors that have been designed and assayed to date with the hope of obtaining new antibacterial compounds.

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Dual Inhibitor of MurD and MurE Ligases from Escherichia coli and Staphylococcus aureus

Cited by 47 publications

References 29 publications

5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

A Detailed Study of Antibacterial 3‐Acyltetramic Acids and 3‐Acylpiperidine‐2,4‐diones

MurD enzymes: some recent developments

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