Design, synthesis, and biological evaluation of 1‐ethyl‐3‐(thiazol‐2‐yl)urea derivatives as <i>Escherichia coli</i> DNA gyrase inhibitors

Tomašič, Tihomir; Barančoková, Michaela; Zidar, Nace; Ilaš, Janez; Tammela, Päivi; Kikelj, D.

doi:10.1002/ardp.201700333

Cited by 16 publications

(13 citation statements)

References 33 publications

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“…However, the enzymatic activities were also still too low to provide any antibacterial activities. When the pyrrole moiety was substituted with ethylurea, which is frequently found in other GyrB inhibitors, this resulted in less potent compounds with no antibacterial activities [59].…”

Section: Pyrrolamides and Their Analoguesmentioning

confidence: 99%

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

2018

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New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in this search. These are both type II topoisomerases that can cleave both DNA strands, and can thus alter DNA topology during replication or similar processes. Currently, there are no ATP-competitive inhibitors of these two enzymes on the market, as the only aminocoumarin representative, novobiocin, was withdrawn due to safety concerns. The search for novel ATP-competitive inhibitors is a focus of ongoing industrial and academical research. This review summarizes the recent efforts in the design, synthesis and evaluation of GyrB/ParE inhibitors. The various approaches to achieve improved antibacterial activities are described, with particular reference to Gram-negative bacteria.

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Section: Pyrrolamides and Their Analoguesmentioning

confidence: 99%

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

2018

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“…The common structural features were identified, from which several pharmacophore queries were generated and further refined (by varying feature types, number of features and their radius). The selection and validation of the final pharmacophore model were grounded on its performance against a dataset (test set) composed of 90 compounds [ 9 , 10 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] whose activity is well-known (61 active and 30 inactive compounds) (see Supplementary Materials: Figure S3 ). The best pharmacophore query was generated using MOE’s Unified scheme, and contains five features: (i) a hydrogen bond acceptor region; (ii) an aromatic or hydrophobic region; (iii) one hydrophobic region; and (iv) two hydrogen-bond donor regions.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, due to extensive and widespread bacterial resistance to current therapeutics [ 7 ] there is an urgent need to develop more efficient synthetic processes to obtain potential new antibiotics derived from a computer-aided rational design. Aiming for the development of inhibitors for the bacterial target Escherichia coli’s DNA Gyrase B [ 3 , 8 , 9 , 10 ], we have used a pharmacophore model created in the Molecular Operating Environment (MOE) molecular design software (Chemical Computing Group) [ 11 ] to provide insights into the ideal structure of potential antibacterial molecules. Following the analysis of the computational pharmacophore model herein described, we have planned the synthesis of families of potential antibacterial molecules derived from the 1 H -benzimidazole scaffold ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential E. coli DNA Gyrase B Inhibition

2021

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A pharmacophore model for inhibitors of Escherichia coli’s DNA Gyrase B was developed, using computer-aided drug design. Subsequently, docking studies showed that 2,5(6)-substituted benzimidazole derivatives are promising molecules, as they possess key hydrogen bond donor/acceptor groups for an efficient interaction with this bacterial target. Furthermore, 5(6)-bromo-2-(2-nitrophenyl)-1H-benzimidazole, selected as a core molecule, was prepared on a multi-gram scale through condensation of 4-bromo-1,2-diaminobenzene with 2-nitrobenzaldehyde using a sustainable approach. The challenging functionalization of the 5(6)-position was carried out via palladium-catalyzed Suzuki–Miyaura and Buchwald-Hartwig amination cross-coupling reactions between N-protected-5-bromo-2-nitrophenyl-benzimidazole and aryl boronic acids or sulfonylanilines, with yields up to 81%. The final designed molecules (2-(aminophen-2-yl)-5(6)-substituted-1H-benzimidazoles), which encompass the appropriate functional groups in the 5(6)-position according to the pharmacophore model, were obtained in yields up to 91% after acid-mediated N-boc deprotection followed by Pd-catalyzed hydrogenation. These groups are predicted to favor interactions with DNA gyrase B residues Asn46, Asp73, and Asp173, aiming to promote an inhibitory effect.

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“…In recent years, we have investigated and reported on several structural types of ATP-competitive GyrB/ParE inhibitors [ 15 , 16 , 17 , 18 , 19 ]. Recently, we also reported the discovery of GyrB inhibitor/ ciprofloxacin hybrids [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation

et al. 2020

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The discovery of multi-targeting ligands of bacterial enzymes is an important strategy to combat rapidly spreading antimicrobial resistance. Bacterial DNA gyrase and topoisomerase IV are validated targets for the development of antibiotics. They can be inhibited at their catalytic sites or at their ATP binding sites. Here we present the design of new hybrids between the catalytic inhibitor ciprofloxacin and ATP-competitive inhibitors that show low nanomolar inhibition of DNA gyrase and antibacterial activity against Gram-negative pathogens. The most potent hybrid 3a has MICs of 0.5 µg/mL against Klebsiella pneumoniae, 4 µg/mL against Enterobacter cloacae, and 2 µg/mL against Escherichia coli. In addition, inhibition of mutant E. coli strains shows that these hybrid inhibitors interact with both subunits of DNA gyrase (GyrA, GyrB), and that binding to both of these sites contributes to their antibacterial activity.

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Design, synthesis, and biological evaluation of 1‐ethyl‐3‐(thiazol‐2‐yl)urea derivatives as Escherichia coli DNA gyrase inhibitors

Cited by 16 publications

References 33 publications

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

Synthesis of Computationally Designed 2,5(6)-Benzimidazole Derivatives via Pd-Catalyzed Reactions for Potential E. coli DNA Gyrase B Inhibition

Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation

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