Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue

Li, Zhiwen; Lü, Xi; Wang, Yanxiang; Hu, Xinxin; Fu, Haigen; Gao, Lei; You, Xuefu; Tang, Sheng; Song, Dan–Qing

doi:10.1016/j.bioorg.2019.103487

Cited by 11 publications

(22 citation statements)

References 27 publications

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“…However, none of them has been clinically approved [8,15]. These are natural plant-based compounds [16,17], synthetic low molecular weight inhibitors [10,[18][19][20][21][22], β-lactams [23][24][25][26], amino acid derivatives and peptides [27]. Boron-based inhibitors attract special attention [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Krivitskaya

Khrenova

2021

Molecules

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Boronic acids are prospective compounds in inhibition of metallo-β-lactamases as they form covalent adducts with the catalytic hydroxide anion in the enzymatic active site upon binding. We compare this chemical reaction in the active site of the New Delhi metallo-β-lactamase (NDM-1) with the hydrolysis of the antibacterial drug imipenem. The nucleophilic attack occurs with the energy barrier of 14 kcal/mol for imipenem and simultaneously upon binding a boronic acid inhibitor. A boron atom of an inhibitor exhibits stronger electrophilic properties than the carbonyl carbon atom of imipenem in a solution that is quantified by atomic Fukui indices. Upon forming the prereaction complex between NDM-1 and inhibitor, the lone electron pair of the nucleophile interacts with the vacant p-orbital of boron that facilitates the chemical reaction. We analyze a set of boronic acid compounds with the benzo[b]thiophene core complexed with the NDM-1 and propose quantitative structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated descriptors of electron density. These relations are applied to classify other boronic acids with the same core found in the database of chemical compounds, PubChem, and proposed ourselves. We demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid inhibitors are 30–70 μM.

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Section: Introductionmentioning

confidence: 99%

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Krivitskaya

Khrenova

2021

Molecules

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“…General Information. All reagents and solvents were purchased from Shanghai Sun Chemical Technology Co., Ltd. 1 H and 13 C NMR spectra were recorded using a Bruker AM-400 (Bruker Company) spectrometer with TMS as an internal standard. Mass spectra were recorded using a Bruker Daltonics APEXII49e spectrometer (Bruker Daltonics Inc.) with an ESI source for ionization.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…The physical data, 1 H NMR, 13 C NMR, and MS of the target compounds are provided in the Supporting Information.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…Natural products have long been explored because their unique molecular structures provide medicinal chemists with invaluable inspiration for drug design . Currently, discovering novel lead compounds from natural products to improve the efficacy and counteract drug resistance is still recognized as one of the most effective strategies. , For example, the cryptolepine alkaloid, isolated mainly from the roots of the West African climbing shrub Cryptolepis sanguinolenta, , has been studied by many groups due to its various biological activities, , such as antimalarial, − antihyperglycemic, anticancer, − anti-inflammatory, , and so on. , In our previous work, cryptolepine showed good fungicidal activities against Botrytis cinerea (B. cinerea) and S.…”

Section: Introductionmentioning

confidence: 99%

“…11 Currently, discovering novel lead compounds from natural products to improve the efficacy and counteract drug resistance is still recognized as one of the most effective strategies. 12,13 For example, the cryptolepine alkaloid, isolated mainly from the roots of the West African climbing shrub Cryptolepis sanguinolenta, 14,15 has been studied by many groups due to its various biological activities, 14,16 such as antimalarial, 17−19 antihyperglycemic, 20 anticancer, 21−23 anti-inflammatory, 24,25 and so on. 26,27 In our previous work, cryptolepine showed good fungicidal activities against Botrytis cinerea (B. cinerea) and S. sclerotiorum, with EC 50 values of 0.0410 and 8.21 μg/mL, respectively, but poor antifungal activities against Fusarium graminearum (F. graminearum) and Rhizoctonia solani (R. solani), with EC 50 values exceeding 30.0 μg/mL.…”

Section: ■ Introductionmentioning

confidence: 99%

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Design, Synthesis, and Antimicrobial Activity of Quindoline Derivatives Inspired by the Cryptolepine Alkaloid

Chu

Tang

et al. 2022

J. Agric. Food Chem.

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Based on the structural characteristics of the cryptolepine alkaloid, a series of new quindoline derivatives bearing various substituents were prepared and evaluated for their fungicidal and antibacterial activities. Bioassay results showed that compound D7 displayed superior in vitro fungicidal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Rhizoctonia solani with EC50 values of 0.780, 3.62, 1.59, and 2.85 μg/mL, respectively. Compound A7 showed apparent antibacterial activities toward Xanthomonas oryzae pv. oryzae with a minimum inhibitory concentration (MIC) value of 3.12 μg/mL. Significantly, in vivo antifungal activity suggested that the curative effect (98.3%) of compound D7 was comparable to that of the positive control azoxystrobin (96.7%) at 100 μg/mL. Preliminary mechanistic studies showed that compound D7 might cause mycelial abnormality of S. sclerotiorum, cell membrane breakage, accumulation of reactive oxygen species (ROS), and inhibition of sclerotia formation. Therefore, compound D7 could be a novel broad-spectrum fungicidal candidate against plant fungal diseases.

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Synthesis of Uscharin Oxime Analogues and Their Biological Evaluation as HIF‐1 Inhibitors

et al. 2020

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Uscharin-like non-classical cardenolides are considered to be useful as HIF-1 inhibitors in the treatment of cancers. To develop more potent HIF-1 inhibitors, oximes and oxime ethers of uscharin were designed and synthesized. Oximation of uscharin exhibited unexpectedly a regioselectivity and stereoselectivity at 3'-thiazoline but not at the 19-aldehyde group, since either E-ketoxime derivative 2 or its ether 5 at C-3' was found as the only product during oximation of uscharin using hydroxylamine or methoxyamine at room temperature. Two 19-aldoxime derivatives 4 and 6 were also synthesized. Ketoxime analogue 2 showed more potent inhibitory effect on HIF-1 transcriptional activity than the parental uscharin. Ketoxime ether 5 and 19-aldoxime 6 exhibited stronger HIF-1 suppressing effect than digoxin (the positive control drug). Moreover, ketoxime derivative 2 displayed the most potent anti-proliferative activity against MCF-7 cancer cells among all compounds. An analysis of structure-activity relationship revealed that 3'-ketoxime is a superior moiety to a thiazoline ring, while 19-aldoxime is inferior to an aldehyde counterpart. Our findings may provide some guidance for the rational design of uscharin-based promising HIF-1 inhibitors.

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Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue

Cited by 11 publications

References 27 publications

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Design, Synthesis, and Antimicrobial Activity of Quindoline Derivatives Inspired by the Cryptolepine Alkaloid

Synthesis of Uscharin Oxime Analogues and Their Biological Evaluation as HIF‐1 Inhibitors

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