- Bioisosteric investigation of ebselen: Synthesis and in vitro characterization of 1,2-benzisothiazol-3(2H)-one derivatives as potent New Delhi metallo-β-lactamase inhibitors
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Carbapenem-resistant Enterobacteriaceae (CRE) producing New Delhi metallo-β-lactamase (NDM-1) cause untreatable bacterial infections, posing a significant threat to human health. In the present study, by employing the concept of bioisosteric replacement of the selenium moiety of ebselen, we have designed, synthesized and characterized a small compound library of 2-substituted 1,2-benzisothiazol-3(2H)-one derivatives and related compounds for evaluating their cytotoxicity and synergistic activity in combination with meropenem against the E. coli Tg1 (NDM-1) strain. The most promising compound 3a demonstrated potent synergistic activity against a panel of clinically isolated NDM-1 positive CRE strains with FICI as low as 0.09. Moreover, its IC50 value and inhibition mechanism were also confirmed by using the enzyme inhibition assay and the ESI-MS analysis respectively. Importantly, compound 3a has acceptable toxicity and is not a PAINS. Because of its structural simplicity and potent synergistic activity in combination with meropenem, we propose that compound 3a may be a promising meropenem adjuvant and a new series of such compounds may worth further investigations.
- Jin, Wen Bin,Xu, Chen,Cheung, Qipeng,Gao, Wei,Zeng, Ping,Liu, Jun,Chan, Edward W.C.,Leung, Yun-Chung,Chan, Tak Hang,Wong, Kwok-Yin,Chen, Sheng,Chan, Kin-Fai
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- 1,2-BENZISOSELENAZOL-3(2H)-ONE AND 1,2-BENZISOTHIAZOL-3(2H)-ONE DERIVATIVES AS BETA-LACTAM ANTIBIOTIC ADJUVANTS
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Provided herein are compositions and methods useful in the treatment of beta-lactam antibiotic resistant bacteria.
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Paragraph 0343; 0344
(2019/10/04)
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- Synthesis and antibacterial activity of isothiazolyl oxazolidinones and analogous 3(2H)-isothiazolones
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The synthesis and antibacterial activity of several new 5-((3-oxoisothiazol-2(3H)-yl)methyl)-3-phenyloxazolidin-2-ones 8 and analogous 2-(4-substituted phenyl)-3(2H)-isothiazolones 3 and 4 substituted at 4 and/or 3-positions of the phenyl moiety with different groups of which some have shown to increase the antibacterial activity of both 3-aryl-2-oxazolidinones and 3(2H)-isothiazolones is described. The most active compounds were isothiazolyl oxazolidinones 8a,j with unsubstituted and 8b with 4-F substituted phenyl rings which showed activities higher than analogous 3(2H)-isothiazolones and comparable or superior to linezolid, vancomycin, and ciprofloxacin against some tested microorganisms. The change in position of F and/or the use of larger substituents gave compounds with reduced or no activity. Evaluation of cytotoxicity to mouse fibroblast (NIH/3T3) cells indicated that these compounds exhibit antibacterial activity at non-cytotoxic concentrations.
- Adibpour, Neda,Khalaj, Ali,Rajabalian, Saeed
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scheme or table
p. 19 - 24
(2010/03/24)
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- Synthesis and antibacterial activity of 2-(4-substituted phenyl)-3(2H)-isothiazolones
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Several new and known 2-(4-substituted phenyl)-3(2H)-isothiazolone derivatives with or without chloro substituent at C-5 position were synthesized and their in vitro antibacterial activity against selected Gram-negative and Gram-positive bacteria were eva
- Khalaj, Ali,Adibpour, Neda,Shahverdi, Ahmad Reza,Daneshtalab, Mohsen
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p. 699 - 705
(2007/10/03)
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- Facile synthesis of N-substituted isothiazol-3(2H)-ones using a hypervalent iodine(III) reagent
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Treatment of N-substituted (Z)-3-(benzylsulfanyl)propenamides (4) with phenyliodine(III) bis(trifluoroacetate) containing trifluoroacetic acid resulted in an interrupted Pummerer-type reaction to give N-substituted isothiazol-3(2H)-ones (5) rather than th
- Kang, Iou-Jiun,Wang, Huey-Min,Huang, Hsin-Yu,Chen, Ling-Ching
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p. 1185 - 1188
(2007/10/03)
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- SYNTHESIS OF 2-SUBSTITUTED 3(2H)-ISOTHIAZOLONES FROM 2-SUBSTITUTED 5-AROYL-3(2H)-ISOTHIAZOLONES
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2-Substituted 3(2H)-isothiazolones 3 have been prepared from 2-substituted 5-aroyl-3(2H)-isothiazolones 6, which are readily available from N-substituted 3-aroylpropionamides 5.The nucleophilic displacement on the 5-aroyl group was found to proceed easily and quantitatively when a benzene solution of compound 6 was stirred at room temperature either with 10percent sodium hydroxide solution or with solid sodium hydroxide.
- Tsolomitis, Athanase,Sandris, Constantine
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p. 569 - 575
(2007/10/02)
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