Design and synthesis of quinolinium-based derivatives targeting FtsZ for antibacterial evaluation and mechanistic study

Zhong, Dong‐Xiao; She, Meng‐Ting; Guo, Xiao-Chun; Zheng, Bo-Xin; Huang, Xuan-He; Zhang, Yihan; Ser, Hooi‐Leng; Wong, Wing‐Leung; Sun, Ning; Lu, Yu‐Jing

doi:10.1016/j.ejmech.2022.114360

Cited by 11 publications

(5 citation statements)

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“…11 Zhong et al identified that A3, a small-molecule inhibitor targeting the FtsZ protein, exhibits potent antibacterial activity against S. aureus, Staphylococcus epidermidis, and E. faecalis without inducing resistance easily. 12 Furthermore, Sortase A is a crucial target for small molecule inhibitors. Promising alternative antimicrobial agents include Sortase A inhibitors such as 2-(2-phenylhydrazinylidene) alkanoates, 13 pyridazinones, 14 and 2-phenylthiazoles.…”

Section: ■ Introductionmentioning

confidence: 99%

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Analyses of the Antibiofilm Activity of o-Phenanthroline Monohydrate against Enterococcus faecalis and Staphylococcus aureus and the Mechanisms Underlying These Effects

Wang,

Wu,

Wang

et al. 2024

ACS Infect. Dis.

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Enterococcus faecalis and Staphylococcus aureus exhibit robust biofilm formation capabilities, the formation of which is closely linked to pathogenicity and drug resistance, thereby resulting in host infection and treatment failure. o-Phenanthroline monohydrate (o-Phen) and its derivatives demonstrate a wide range of antibacterial and antifungal activities. In this study, we aimed to explore the antibiofilm activity of o-Phen to E. faecalis and S. aureus and provide insights into the molecular mechanisms for combating biofilm resistance. We demonstrated that o-Phen possesses significant antibacterial and antibiofilm properties against E. faecalis and S. aureus, inducing alterations in bacterial morphology, compromising cell membrane integrity, and exhibiting synergistic effects with β-lactam antibiotics at sub-MIC concentrations. The adhesion ability and automatic condensation capacity of, and synthesis of, extracellular polymers by E. faecalis cells were reduced by o-Phen, resulting in the inhibition of biofilm formation. Importantly, transcriptome analysis revealed 354 upregulated and 456 downregulated genes in o-Phen-treated E. faecalis. Differentially expressed genes were enriched in 11 metabolism-related pathways, including amino acid metabolism, pyrimidine metabolism, and glycolysis/gluconeogenesis. Moreover, the oppA, CeuA, and ZnuB genes involved in the ABC transport system, and the PBP1A penicillin-binding protein-coding genes sarA and mrcA were significantly downregulated. The multidrug efflux pump system and membrane permeability genes mdtG and hlyD, and bacterial adhesion-related genes, including adcA and fss2 were also downregulated, while mraZ and ASP23 were upregulated. Thus, o-Phen is anticipated to be an effective alternative drug for the treatment of E. faecalis and S. aureus biofilm-associated infections.

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Section: ■ Introductionmentioning

confidence: 99%

“…aureus, Staphylococcus epidermidis, and E. faecalis without inducing resistance easily . Furthermore, Sortase A is a crucial target for small molecule inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Analyses of the Antibiofilm Activity of o-Phenanthroline Monohydrate against Enterococcus faecalis and Staphylococcus aureus and the Mechanisms Underlying These Effects

Wang,

Wu,

Wang

et al. 2024

ACS Infect. Dis.

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“…Consequently, there is an attendant interest in the development of flexible, and efficient routes to synthesis of pyridin-4(1 H )-imines. Unfortunately, the adaptation of such chemistry to the synthesis of pyridin-4(1 H )-imines was rare so that the only synthesis method available is the nucleophilic substitution reaction of 4-aminopyridine with halides (Scheme a) . Therefore, the development of novel methods to construct the pyridin-4(1 H )-imine skeleton is important in the field of organic synthesis and pharmaceutical chemistry.…”

Section: Introductionmentioning

confidence: 99%

Chemoselectivity of the CuAAC/Ring Cleavage/Cyclization Reaction between Enaminones and α-Acylketenimine

Li,

Luo,

Luo

et al. 2024

J. Org. Chem.

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Ketenimines represent an important class of reactive species, useful synthetic intermediates, and synthons. However, in general, ketenimines preferentially undergoes nucleophilic addition reactions with hydroxyl and amino groups, and carbon functional groups remain a less studied subset of such systems. Herein, we develop a straightforward syntheses of pyridin-4(1H)-imines that is achieved by cyclization of a reacting enaminone unit with αacylketenimine which is generated from the reactions of sulfonyl azides and terminal ynones in situ (CuAAC/Ring cleavage reaction). The cascade process preferentially starts with the nucleophilic α-C of the enaminone unit instead of an amino group, attacking the electron-deficient central carbon of ketenimine, and the chemoselectivity unconventional products pyridin-4(1H)-imines were formed by intramolecular cyclization.

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“…Preliminary mechanistic exploration suggests that compounds 6a-6d are potent FtsZ inhibitors, which block the GTPase activity of FtsZ (filamentous temperature-sensitive mutant Z), leading to the inhibition of bacterial cell division [15]. The FtsZ protein, playing a key role in bacterial cell division, has recently been identified as an attractive target in the development of new antibacterial drugs [16][17][18][19][20]. At the same time, 9-phenylfascaplysin (7) and a series of its derivatives can be considered as analogs of FtsZ inhibitor 6a (Figure 2) [21].…”

Section: Introductionmentioning

confidence: 99%

Comparative Evaluation of the Antibacterial and Antitumor Activities of 9-Phenylfascaplysin and Its Analogs

Zhidkov,

Sidorova,

Smirnova

et al. 2024

Marine Drugs

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Based on the results of our own preliminary studies, the derivative of the marine alkaloid fascaplysin containing a phenyl substituent at C-9 was selected to evaluate the therapeutic potential in vivo and in vitro. It was shown that this compound has outstandingly high antimicrobial activity against Gram-positive bacteria, including antibiotic-resistant strains in vitro. The presence of a substituent at C-9 of the framework is of fundamental importance, since its replacement to neighboring positions leads to a sharp decrease in the selectivity of the antibacterial action, which indicates the presence of a specific therapeutic target in bacterial cells. On a model of the acute bacterial sepsis in mice, it was shown that the lead compound was more effective than the reference antibiotic vancomycin seven out of nine times. However, ED50 value for 9-phenylfascaplysin (7) was similar for the unsubstituted fascaplysin (1) in vivo, despite the former being significantly more active than the latter in vitro. Similarly, assessments of the anticancer activity of compound 7 against various variants of Ehrlich carcinoma in mice demonstrated its substantial efficacy. To conduct a structure–activity relationship (SAR) analysis and searches of new candidate compounds, we synthesized a series of analogs of 9-phenylfascaplysin with varying aryl substituents. However, these modifications led to the reduced aqueous solubility of fascaplysin derivatives or caused a loss of their antibacterial activity. As a result, further research is required to explore new avenues for enhancing its pharmacokinetic characteristics, the modification of the heterocyclic framework, and optimizing of treatment regimens to harness the remarkable antimicrobial potential of fascaplysin for practical usage.

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Design and synthesis of quinolinium-based derivatives targeting FtsZ for antibacterial evaluation and mechanistic study

Cited by 11 publications

References 50 publications

Analyses of the Antibiofilm Activity of o-Phenanthroline Monohydrate against Enterococcus faecalis and Staphylococcus aureus and the Mechanisms Underlying These Effects

Analyses of the Antibiofilm Activity of o-Phenanthroline Monohydrate against Enterococcus faecalis and Staphylococcus aureus and the Mechanisms Underlying These Effects

Chemoselectivity of the CuAAC/Ring Cleavage/Cyclization Reaction between Enaminones and α-Acylketenimine

Comparative Evaluation of the Antibacterial and Antitumor Activities of 9-Phenylfascaplysin and Its Analogs

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