Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies

Zhao, Dongmei; Zhao, Shizhen; Zhao, Liyu; Zhang, Xiangqian; Peng, Wei; Liu, Chunchi; Sun, Bin; X, Su; Cheng, Maosheng

doi:10.1016/j.bmc.2016.11.051

Cited by 51 publications

(19 citation statements)

References 27 publications

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“…It was reported that tetraphenyl imidazole derivatives could self-assemble into nanoparticles for chemical sensing or imaging of gram-positive bacterial strains 65 , 66 . In this study, inspired by the antimicrobial activity of the imidazole moiety 67 - 69 and the excellent antibacterial effect of quaternary ammonium compounds 70 - 72 , we designed a cationic bola-type small molecule by combining tetraphenyl imidazole core with quaternary ammonium group ( TPIP ) for fast microbial detection and bacterial infection treatment. TPIP is composed of three components ( Scheme 1 ): (1) the substituted imidazole is used as the AIEgen with antibacterial activity, (2) the alkyl chain can tune the spatial positioning of the positive charge in molecules and reduce the toxicity of small cationic molecules, and (3) the pyridinium salt group serving as the hydrophilic terminal group has an antimicrobial effect.…”

Section: Introductionmentioning

confidence: 99%

Novel Self-assembled Organic Nanoprobe for Molecular Imaging and Treatment of Gram-positive Bacterial Infection

Tang¹,

Zeng²,

Xu³

et al. 2018

Theranostics

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Background: Increasing bacterial infections as well as a rise in bacterial resistance call for the development of novel and safe antimicrobial agents without inducing bacterial resistance. Nanoparticles (NPs) present some advantages in treating bacterial infections and provide an alternative strategy to discover new antibiotics. Here, we report the development of novel self-assembled fluorescent organic nanoparticles (FONs) with excellent antibacterial efficacy and good biocompatibility.Methods: Self-assembly of 1-(12-(pyridin-1-ium-1-yl)dodecyl)-4-(1,4,5-triphenyl-1H-imidazol-2-yl)pyridin-1-ium (TPIP) in aqueous solution was investigated using dynamic light scattering (DLS) and transmission electron microscopy (TEM). The bacteria were imaged under a laser scanning confocal microscope. We evaluated the antibacterial efficacy of TPIP-FONs in vitro using sugar plate test. The antimicrobial mechanism was explored by SEM. The biocompatibility of the nanoparticles was examined using cytotoxicity test, hemolysis assay, and histological staining. We further tested the antibacterial efficacy of TPIP-FONs in vivo using the S. aureus-infected rats.Results: In aqueous solution, TPIP could self-assemble into nanoparticles (TPIP-FONs) with characteristic aggregation-induced emission (AIE). TPIP-FONs could simultaneously image gram-positive bacteria without the washing process. In vitro antimicrobial activity suggested that TPIP-FONs had excellent antibacterial activity against S. aureus (MIC = 2.0 µg mL-1). Furthermore, TPIP-FONs exhibited intrinsic biocompatibility with mammalian cells, in particular, red blood cells. In vivo studies further demonstrated that TPIP-FONs had excellent antibacterial efficacy and significantly reduced bacterial load in the infectious sites.Conclusion: The integrated design of bacterial imaging and antibacterial functions in the self-assembled small molecules provides a promising strategy for the development of novel antimicrobial nanomaterials.

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Section: Introductionmentioning

confidence: 99%

Novel Self-assembled Organic Nanoprobe for Molecular Imaging and Treatment of Gram-positive Bacterial Infection

Tang¹,

Zeng²,

Xu³

et al. 2018

Theranostics

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“…In addition, it has also been recognized [ 15 ] that many imidazole-containing ligands could exhibit large chemical-shift variations when bound to a molecular target, such as a protein, offering valuable information about changes in the local structure of the ligand or target. Among others, imidazole core structures are found in different carboxypeptidase, hemeoxygenase and β-lactamase inhibitors [ 16 , 17 ] as well as among compounds with anti-inflammatory, anticancer, antibacterial, antifungal, antitubercular, antidiabetic and antiviral activity [ 18 , 19 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Imidazole Aldoximes with Broad-Spectrum Antimicrobial Potency against Multidrug Resistant Gram-Negative Bacteria

et al. 2018

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In the search for a new class of potential antimicrobial agents, five novel N-substituted imidazole 2-aldoximes and their six quaternary salts were evaluated. The antimicrobial activity was assessed against a panel of representative Gram-positive and Gram-negative bacteria, including multidrug resistant bacteria. All compounds demonstrated potent in vitro activity against the tested microorganisms, with MIC values ranging from 6.25 to 50.0 μg/mL. Among the tested compounds, two quaternary compounds (N-but-3-enyl- and meta- (10) or para- N-chlorobenzyl (11) imidazolium 2-aldoximes) displayed the most potent and broad-spectrum activity against both Gram-positive and Gram-negative bacterial strains. The broth microdilution assay was also used to investigate the antiresistance efficacy of the both most active compounds against a set of Enterobacteriaceae isolates carried a multiple extended-spectrum β-lactamases (ESBLs) in comparison to eight clinically relevant antibiotics. N-but-3-enyl-N-meta-chlorobenzyl imidazolium 2-aldoxime was found to possess promising antiresistance efficacy against a wide range of β-lactamases producing strains (MIC 2.0 to 16.0 μg/mL). Best results for that compound were obtained against Escherichia coli and Enterobacter cloacae producing multiple β-lactamases form A and C molecular classes, which were 32- and 128-fold more potent than ceftazidime and cefotaxime, respectively. To visualize the results, principal component analysis was used as an additional classification tool. The mixture of ceftazidime and compound 10 (3 μg:2 μg) showed a strong activity and lower the necessary amount (up to 40-fold) of 10 against five of ESBL-producing isolates (MIC ≤ 1 µg/mL).

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“…[8][9][10] Other important Nβ-substituted α,β-diamino acids are some analogous of histidine, such as β-(1-pyrazolyl)alanine or β-(1-triazolyl)alanine, that involve the substitution of imidazole ring by pyrazole or triazole, respectively, and have been used for diabetes treatment. [11][12][13] These compounds have been accessed by N-nucleophilic displacement of β-haloalanine derivatives, 14 by ring-opening of aziridines, 15 lactones 16 or cyclic sulfamidates, 17 or by chemoenzymatic synthesis using N-Michael addition on dehydroalanines (Dha). 18 On the other hand, 1-isohistidine is another analog also bearing an imidazole ring but with a different substitution pattern.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N_β-Substituted α,β-Diamino Acids via Stereoselective N-Michael Additions to a Chiral Bicyclic Dehydroalanine

et al. 2020

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The highly diastereoselective 1,4-conjugate additions of several nitrogen nucleophiles to chiral bicyclic dehydroalanines have been assessed effectively at room temperature in good to excellent yields without needing any catalyst or additional base. This methodology is general, simple, oxygen and moisture tolerant, high-yielding, totally chemo-and stereoselective. Significantly, most of the reaction adducts were obtained in nearly quantitative yield without column chromatography purification. This procedure offers an efficient and practical approach for the synthesis of Nβ-substituted α,βdiamino acids, such as 1-isohistidine, τ-histidinoalanine, β-benzylaminoalanine, β-(piperidin-1-yl)alanine, β-(azepan-1-yl)alanine and fluorescent and ciprofloxacincontaining amino acid derivatives.

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Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies

Cited by 51 publications

References 27 publications

Novel Self-assembled Organic Nanoprobe for Molecular Imaging and Treatment of Gram-positive Bacterial Infection

Novel Self-assembled Organic Nanoprobe for Molecular Imaging and Treatment of Gram-positive Bacterial Infection

Novel Imidazole Aldoximes with Broad-Spectrum Antimicrobial Potency against Multidrug Resistant Gram-Negative Bacteria

Synthesis of N_β-Substituted α,β-Diamino Acids via Stereoselective N-Michael Additions to a Chiral Bicyclic Dehydroalanine

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Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies

Cited by 51 publications

References 27 publications

Novel Self-assembled Organic Nanoprobe for Molecular Imaging and Treatment of Gram-positive Bacterial Infection

Novel Self-assembled Organic Nanoprobe for Molecular Imaging and Treatment of Gram-positive Bacterial Infection

Novel Imidazole Aldoximes with Broad-Spectrum Antimicrobial Potency against Multidrug Resistant Gram-Negative Bacteria

Synthesis of Nβ-Substituted α,β-Diamino Acids via Stereoselective N-Michael Additions to a Chiral Bicyclic Dehydroalanine

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Synthesis of N_β-Substituted α,β-Diamino Acids via Stereoselective N-Michael Additions to a Chiral Bicyclic Dehydroalanine