Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus

Dong, Jianghong; Li, Runfeng; Cui, Wei; Jiang, Haiming; Ling, Yixia; Yang, Zifeng; Hu, Wenhui

doi:10.1016/j.ejmech.2015.12.013

Cited by 42 publications

(74 citation statements)

References 43 publications

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“…Specifically, an imidazole derivative of pinanamine (19) showed a moderate inhibitory effect against A/WSN/33 (H1N1) in a cytopathic effect inhibition assay (CPE; EC 50 = 95.5 µM). Dong et al (2016) subsequently reported a related compound (20) with improved activity against both WT A/HK/68 (H3N2) as well as A/WSN/33 (H1N1) encoding M2 Ser31Asn with EC 50 s of 2.5 and 3.4 µM, respectively.…”

Section: Non-adamantane-based Inhibitorsmentioning

confidence: 99%

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

et al. 2020

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Highlights• The M2 protein of influenza A is a proton-gated proton channel that is required for viral replication • Current influenza strains are resistant to licensed M2 antivirals, so new therapies that target M2 are needed • The structure and function of M2, rise of drug resistance mutations, and current antiviral strategies are discussed AbstractThe ongoing threat of seasonal and pandemic influenza to human health requires antivirals that can effectively supplement existing vaccination strategies. The M2 protein of influenza A virus (IAV) is a proton-gated, proton-selective ion channel that is required for virus replication and is an established antiviral target. While licensed adamantane-based M2 antivirals have been historically used, M2 mutations that confer major adamantane resistance are now so prevalent in circulating virus strains that these drugs are no longer recommended. Here we review the current understanding of IAV M2 structure and function, mechanisms of inhibition, the rise of drug resistance mutations, and ongoing efforts to develop new antivirals that target resistant forms of M2.

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Section: Non-adamantane-based Inhibitorsmentioning

confidence: 99%

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

et al. 2020

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“…Based on several literature surveys, imidazole-based small molecules have been described as promising pharmaceutical agents in view of their unique bioactivity patterns, ranging from antioxidant, anti-inflammatory, analgesic, and neuroprotective to chemotherapeutic and anti-HIV activities [ 8 , 9 , 10 , 11 ]. Imidazoles and in particular their salts comprise a boundless and emerging field, due to not only their favourable properties such as excellent bioavailability, good tissue penetrability and permeability but also a relatively low incidence of adverse and toxic effects [ 12 ]. So far, many imidazole-based derivatives ( Figure 1 ) have been successfully developed and employed as clinical drugs [ 13 ].…”

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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“…As an important heterocyclic moiety, the imidazole ring could be found in many natural products, pharmaceutical compounds, functional materials [ 6 , 7 ] (dyes, optoelectronics [ 8 ]). Besides, the diversity of biological activities of imidazole derivatives ranges from antibacterial, antifungal [ 9 ], anti-inflammatory, antitumor, and antimalarial activity [ 10 ] to monoamine oxidase inhibition [ 11 ] and many more [ 12 , 13 ], including the biological activity of metal complexes of some N -heterocyclic carbenes derived from imidazoles [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…The 2-phenylimidazoles, for example, are mostly studied for their biological activity, and often the structural characterizations are scarce [ 13 ]. One major reason in some of the cases could be the fast tautomerization of the imidazole ring leading to very broad and weak 13 C-NMR signals in the solution NMR spectra.…”

Section: Introductionmentioning

confidence: 99%

“…Herein, we focus our study on 2-phenylimidazolecarbaldehydes, some of which had previously been exploited as synthons for synthesis of Schiff bases [ 29 , 30 ] or various biologically active molecules [ 13 ], but their structure had scarcely been characterized. To the best of our knowledge, there is no crystallographic data reported on 2-phenylimidazolecarbaldehydes and the corresponding methanols, and the available structural descriptions are based solely on 1 H-NMR spectra, without 13 C-NMR measurements and complete assignments.…”

Section: Introductionmentioning

confidence: 99%

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13C CPMAS NMR as a Tool for Full Structural Description of 2-Phenyl Substituted Imidazoles That Overcomes the Effects of Fast Tautomerization

et al. 2020

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Tautomerization of 2-phenylimidazolecarbaldehydes has not been studied in detail so far, although this process is a well-known phenomenon for imidazole derivatives. That is why we focus our study on a series of 2-phenylimidazolecarbaldehydes and their parent alcohols that were synthesized and studied by detailed 1H and 13C NMR in solution and in the solid state. The apparent problem is that the fast tautomerization impedes the full structural description of the compounds by conventional 13C NMR measurements. Indeed, the 13C NMR spectra in solution exhibit poor resolution, and in most cases, signals from the imidazole ring are not detectable. To avoid this problem, we used 13C CP-MAS NMR as an alternative spectroscopic method for unambiguous spectroscopic characterization of the studied series of 2-phenylimidazoles. The data were analyzed in combination with quantum chemical DFT-GIAO methods by considering the tautomerization process and the intermolecular interactions. The DFT (B3LYP/6-31G(d,p)) calculations allowed to identify and suggest the preferred tautomer in the gas phase and in DMSO solvent, which for alcohols are (2-phenyl-1H-imidazol-4-yl)methanol and its analogs, and for the aldehydes are the 2-phenyl-1H-imidazole-5-carbaldehydes. The gas-phase calculated energy differences between the two possible tautomeric forms are in the range 0.645–1.415 kcal/mol for the alcohols and 2.510–3.059 kcal/mol for the aldehydes. In the DMSO solvent, however, for all compounds, the calculated energy differences go below 1.20 kcal/mol. These data suggest that both tautomeric forms of the studied 2-phenylimidazoles can be present in solution at room temperature. Our data from detailed 2D NMR measurements in the solid state (1H-13C HETCOR and 1H-1H double-quantum coherence MAS NMR) suggested that also in the solid state both tautomers coexist in different crystalline domains. This fact does not obscure the 13C CP-MAS NMR spectra of the studied 2-phenyl substituted imidazoles and suggests this spectroscopic method as a powerful tool for a complete structural description of tautomeric systems with aromatic conjugation.

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Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus

Cited by 42 publications

References 43 publications

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

Put a cork in it: Plugging the M2 viral ion channel to sink influenza

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

13C CPMAS NMR as a Tool for Full Structural Description of 2-Phenyl Substituted Imidazoles That Overcomes the Effects of Fast Tautomerization

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