Synthesis and evaluation of cadiolide analogues as inhibitors of bacterial biofilm formation

Mairink, Simone Z.; Barbosa, Luiz C. A.; Boukouvalas, John; Pedroso, S.H.S.P.; Santos, Simone Gonçalves Dos; Magalhães, Paula Prazeres; Farias, Luiz M.

doi:10.1007/s00044-018-2246-1

Cited by 6 publications

(5 citation statements)

References 42 publications

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“…C. violaceum is a Gram-negative bacterium, which utilizes AHLs as signaling mole cules for QS. Hence, this strain is widely used in research work related to QSI screening [25]. Out of twenty-three amidocoumarins tested, six compounds S1-S6 (Figure S1 showed anti-QS activity with zones of inhibition 14, 15, 14, 12, 16 and 14 mm, respec tively, against C. violaceum.…”

Section: Inhibitor Designmentioning

confidence: 99%

“…El-Messery et al described the antibiofilm activity of some amide chalcones, with IC 50 values ranging from 2.4 to 8.6 µg/mL [24]. Certain cadiolide analogs also inhibited biofilm formation in Staphylococcus aureus and Enterococcus faecalis at low concentrations [25]. In a recent contribution, trifluoromethyl substituted salicylanilide derivative has been reported to reduce preformed biofilm in S. aureus better than vancomycin [26].…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and In Vitro Studies of 3-Amidocoumarins as Novel Antibiofilm Agents

Sharma

Singh²,

Raghuvanshi

et al. 2023

DDC

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Pseudomonas aeruginosa, a life-threatening bacteria listed as a priority pathogen by World Health Organization WHO, is known to cause severe nosocomial infections and fatality in immunocompromised individuals through its quorum sensing (QS) mediated biofilm formation. P. aeruginosa’s antibiotic-resistant biofilms are highly challenging to the existing antibiotic treatment options. There is an urgent clinical need to develop novel alternative therapeutic molecules such as antibiofilm and antiquorum sensing agents to counter the emergence of an unprecedented pace of antibiotic resistance of pathogens. In this context, a library of seventy 3-amidocoumarin derivatives was designed, and docking studies were performed against the P. aeruginosa LasR receptor using AutoDock 4.0. Based on docking results, a final series of sixteen 3-amidocoumarin derivatives (4a–p) were synthesized and evaluated for antibiofilm activity in vitro. Eight compounds significantly inhibited the formation of P. aeruginosa PAO1 biofilm. Compounds 4f, 4l and 4o showed maximum % inhibition in antibiotic-resistant P. aeruginosa PAO1 biofilm formation in the range of 80% to 86%. Further, the structure–activity relationship (SAR) studies revealed that the presence of electron-donating and bromo substituents at benzamido and coumarin moieties, respectively, effectively enhances the antibiofilm activity. In addition, the binding interactions between the synthesized compounds and active sites of the LasR QS receptor (Protein Data Bank Code: 2uv0) in P. aeruginosa were also investigated by molecular docking. The high binding affinities indicate that these compounds might be suitable for development into potent inhibitors of QS and biofilm disruptors.

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Section: Inhibitor Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and In Vitro Studies of 3-Amidocoumarins as Novel Antibiofilm Agents

Sharma

Singh²,

Raghuvanshi

et al. 2023

DDC

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“…Os compostos 11c e 11d foram sintetizados utilizando o mesmo procedimento experimental descrito para o composto 11b. Os dados físicos e espectroscópicos do composto 11c podem ser encontrados em Mairink et al 27…”

Section: -(3-bromo-4-metoxifenil)-1-(4-metoxifenil)prop-2-in-1-ona (unclassified

Inibição Do Crescimento De Microrganismos Patogênicos Induzida Por Butenolídeos Análogos Aos Cadiolídeos

Mairink

Barbosa

Maltha

et al. 2019

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INHIBITORY EFFECT ON GROWTH OF PATHOGENIC MICROORGANISMS INDUCED BY BUTENOLIDES RELATED TO CADIOLIDES. The increasing number of antibiotic resistant microorganisms requires the development of new drugs. In this context, natural cadiolides are promising leads as they present potent antimicrobial activity and low cytotoxicity. In this work we report the synthesis of 21 new cadiolide analogues. The synthesis involved a Diels−Alder cycloaddition/ cycloreversion reaction between an oxazole and different ynones, affording four intermediate butenolides (14a-d) in 61-81% yield. These intermediates were subjected to a vinylogous Knoevenagel condensation, followed by demethylation of the methoxylated compounds, affording all 21 analogues in good yields. The antibiotic activity of all compounds was evaluated against a panel of five microorganisms. The bioassays on the microbial growth showed that the cadiolides are more active for Gram-positive than Gram-negative bacteria, and have low activity against the fungus C. albicans. The most active compounds (14b, 15b, 15c and 16e) were effective against S. aureus showing IC 50 in the range of 1.8-6.0 µg mL-1. The results also indicated that the nature and position of substituent groups on the aromatic moieties have some effect on the activities.

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“…Interestingly, compounds 6 , 7 , and 8 (Figure ), with an alkyl chain at the C-3 position, despite being less active than 5 , are more likely to be QSIs due to their low toxicity . Cadiolide analog 9 (Figure ), designed and synthesized by Mairink et al, effectively inhibits the biofilm formation of Gram-positive and Gram-negative bacteria with IC 50 values of 7.5 ± 2.6, 3.6 ± 2.1, and 0.7 ± 0.4 μg/mL against Klebsiella pneumoniae , Enterococcus faecalis , and Staphylococcus aureus , respectively, and shows no or low effect on planktonic growth . Our laboratory has tried to design and synthesize aryl-substituted pyrrolidone derivatives and evaluate their QS inhibitory activities.…”

Section: Introductionmentioning

confidence: 99%

“…21 Cadiolide analog 9 (Figure 2), designed and synthesized by Mairink et al, effectively inhibits the biofilm formation of Gram-positive and Gram-negative bacteria with IC 50 values of 7.5 ± 2.6, 3.6 ± 2.1, and 0.7 ± 0.4 μg/mL against Klebsiella pneumoniae, Enterococcus faecalis, and Staphylococcus aureus, respectively, and shows no or low effect on planktonic growth. 22 Our laboratory has tried to design and synthesize aryl-substituted pyrrolidone derivatives and evaluate their QS inhibitory activities. Among them, compound 10 (Figure 2) can effectively interfere with the synthesis of virulence factors and biofilm formation of P. aeruginosa and remarkably reduce their toxicity compared with bromofuranones.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of 4-Fluorophenyl-5-methylene-2(5H)-furanone Derivatives as Potent Quorum Sensing Inhibitors

Zhang

Chen

et al. 2023

J. Med. Chem.

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Quorum sensing inhibitors (QSIs) are a class of compounds that can reduce the pathogenicity of bacteria without affecting bacterial growth. In this study, we designed and synthesized four series of 4fluorophenyl-5-methylene-2(5H)-furanone derivatives and evaluated their QSI activities. Among them, compound 23e not only showed excellent inhibitory activity against various virulence factors but also significantly enhanced the inhibitory activity of antibiotics ciprofloxacin and clarithromycin against two strains of Pseudomonas aeruginosa in vitro. What is even more exciting is that it remarkably increased the antibacterial effect in vivo in combination with ciprofloxacin in the bacteremia model infected with P. aeruginosa PAO1. Moreover, 23e had little hemolytic activity to mouse erythrocytes. Further, the results of GFP reporter fluorescence strain inhibition and β-galactosidase activity inhibition experiments demonstrated that 23e simultaneously targeted the three quorum sensing systems in P. aeruginosa. As a result, compound 23e could be used as an effective QSI for further development against bacterial infections.

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Synthesis and evaluation of cadiolide analogues as inhibitors of bacterial biofilm formation

Cited by 6 publications

References 42 publications

Design, Synthesis and In Vitro Studies of 3-Amidocoumarins as Novel Antibiofilm Agents

Design, Synthesis and In Vitro Studies of 3-Amidocoumarins as Novel Antibiofilm Agents

Inibição Do Crescimento De Microrganismos Patogênicos Induzida Por Butenolídeos Análogos Aos Cadiolídeos

Design and Synthesis of 4-Fluorophenyl-5-methylene-2(5H)-furanone Derivatives as Potent Quorum Sensing Inhibitors

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