Synthesis, biological evaluation and molecular docking of 2-phenyl-benzo[d]oxazole-7-carboxamide derivatives as potential Staphylococcus aureus Sortase A inhibitors

Zhang, Yong; Bao, Jiaqi; Deng, Xinxian; He, Wan; Fan, Jiajun; Jiang, Faqin; Fu, Lei

doi:10.1016/j.bmcl.2016.06.074

Cited by 19 publications

(11 citation statements)

References 15 publications

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“…The effort to discover a Sortase A inhibitor has identified various structural scaffolds as potentially clinical useful solutions. These include: 2-phenylbenzofuran-3-carboxamide [ 18 ], 2-phenylbenzo[ d ]oxazole-7-carboxamide [ 19 ], 2-(2-phenylhydrazinylidene)alkanoic acids [ 20 ], benzisothiazolinone [ 21 ], indolethiazolidine [ 22 ], rhodanines [ 23 ], diarylacrylonitriles, triazolo-thiadiazole [ 24 ], and other structures as presented in the reviews of these fields [ 16 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

et al. 2017

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Sortase A inhibition is a well establish strategy for decreasing bacterial virulence by affecting numerous key processes that control biofilm formation, host cell entry, evasion and suppression of the immune response and acquisition of essential nutrients. A meta-analysis of structures known to act as Sortase A inhibitors provided the starting point for identifying a new potential scaffold. Based on this template a series of new potential Sortase A inhibitors, that contain the 2-phenylthiazole moiety, were synthesized. The physicochemical characterisation confirmed the identity of the proposed structures. Antibacterial activity evaluation showed that the new compounds have a reduced activity against bacterial cell viability. However, the compounds prevent biofilm formation at very low concentrations, especially in the case of E. faecalis. Molecular docking studies performed estimate that this is most likely due to the inhibition of Sortase A. The new compounds could be used as add-on therapies together with known antibacterial agents in order to combat multidrug-resistance enterococcal infections.

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Section: Introductionmentioning

confidence: 99%

New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

et al. 2017

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“…Several significant small organic molecules have been designed and synthesized, as shown in Figure 2 , with promising IC 50 values. Herein, the concrete synthetic features and the analytic properties for structural identification are described in the order of diarylacrylonitriles [ 38 ], pyridazinones [ 39 ], aryl 3-acryloamides [ 40 ], dihydro-β-carboline [ 41 ], benzisothiazolinones [ 42 ], triazolothiadiazoles [ 43 ], 2-(2-phenylhydrazinylidene)alkanoates [ 44 ], 2-phenyl-benzo[ d ]oxazole-7-carboxamide [ 45 ], 2-phenyl-benzofuran-7-carboxamide [ 46 ], 2-phenylthiazoles [ 47 ], 2, 5-disubstitued thiadiazole [ 48 ], and thiadiazolidinedione [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

“…During the search for a new frame of sortase A inhibitors, the Jiang and Fu research group developed L-shaped kinked molecules that mimic the sortase A substrate, LPXTG, sequentially designing 2-phenyl-benzo[d]oxazole-7-carboxamide and 2-phenyl-benzofuran-3-carboxamide [ 45 , 46 ]. Sortase A is known to recognize the LPXTG sorting signal (X means any amino acids) which is arranged in an L-shape mode by the L (Leu) and P (Pro) residues.…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of Small Molecules as Potent Staphylococcus aureus Sortase A Inhibitors

Paek

2020

Antibiotics

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The widespread and uncontrollable emergence of antibiotic-resistant bacteria, especially methicillin-resistant Staphylococcus aureus, has promoted a wave of efforts to discover a new generation of antibiotics that prevent or treat bacterial infections neither as bactericides nor bacteriostats. Due to its crucial role in virulence and its nonessentiality in bacterial survival, sortase A has been considered as a great target for new antibiotics. Sortase A inhibitors have emerged as promising alternative antivirulence agents against bacteria. Herein, the structural and preparative aspects of some small synthetic organic compounds that block the pathogenic action of sortase A have been described.

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“…In 1999, Schneewind and colleagues discovered that Sortase A recognizes the LPXTG motif present at the C-terminus of cell surface proteins and recruits them to the peptidoglycan cell wall building block, lipid II (Mazmanian et al, 1999). The search for molecules that can inhibit Sortase A is one of the promising approaches for the development of innovative strategies to attenuate bacterial virulence (Cascioferro et al, 2015;Bi et al, 2016;Zhang et al, 2016) and biofilm formation (Parrino et al, 2019). Wang et al (2018) demonstrated that an oligopeptide LPRDA can be a potential anti-infective strategy for the treatment of S. aureus infections.…”

Section: Introductionmentioning

confidence: 99%

Sortase A Mediated Bioconjugation of Common Epitopes Decreases Biofilm Formation in Staphylococcus aureus

et al. 2020

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Staphylococcus aureus is one of the most notorious pathogens and is frequently associated with nosocomial infections imposing serious risk to immune-compromised patients. This is in part due to its ability to colonize at the surface of indwelling medical devices and biofilm formation. Combating the biofilm formation with antibiotics has its own challenges like higher values of minimum inhibitory concentrations. Here, we describe a new approach to target biofilm formation by Gram positive bacteria. Sortase A is a transpeptidase enzyme which is responsible for tagging of around ∼22 cell surface proteins onto the outer surface. These proteins play a major role in the bacterial virulence. Sortase A recognizes its substrate through LPXTG motif. Here, we use this approach to install the synthetic peptide substrates on S. aureus. Sortase A substrate mimic, 6His-LPETG peptide was synthesized using solid phase peptide chemistry. Incorporation of the peptide on the cell surface was measured using ELISA. Effect of peptide incubation on Staphylococcus aureus biofilm was also studied. 71.1% biofilm inhibition was observed with 100 µM peptide while on silicon coated rubber latex catheter, 45.82% inhibition was observed. The present work demonstrates the inability of surface modified S. aureus to establish biofilm formation thereby presenting a novel method for attenuating its virulence.

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Synthesis, biological evaluation and molecular docking of 2-phenyl-benzo[d]oxazole-7-carboxamide derivatives as potential Staphylococcus aureus Sortase A inhibitors

Cited by 19 publications

References 15 publications

New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

New 2-Phenylthiazoles as Potential Sortase A Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

Design and Synthesis of Small Molecules as Potent Staphylococcus aureus Sortase A Inhibitors

Sortase A Mediated Bioconjugation of Common Epitopes Decreases Biofilm Formation in Staphylococcus aureus

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