Discovery and structure–activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors

Cooper, Ian; McCarroll, Andrew J.; McGarry, D.H.; Kirkham, James D.; Pichowicz, Mark; Walker, Rolf; Warrilow, Catherine E.; Salisbury, Anne‐Marie; Savage, Victoria J.; Moyo, Emmanuel; Forward, Henry; Cheung, Jonathan; Metzger, Richard; Gault, Zoe; Nelson, Gary; Hughes, Diarmaid; Cao, Sha; Maclean, John; Charrier, Cédric; Craighead, Mark; Best, Stuart; Stokes, Neil R.; Ratcliffe, Andrew J.

doi:10.1016/j.bmcl.2016.07.061

Cited by 10 publications

(4 citation statements)

References 22 publications

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“… 8 The function of DNA gyrase and Topo IV is to maintain DNA in a proper topological state during DNA replication and transcription. 9 Several additional classes of type II bacterial DNA topoisomerase inhibitors have been reported, including 3-aminoquinazolinediones, 10 4 H -4-oxoquinolizines, 8e , 11 isothiazolones, 12 quinolyl-piperidines, 13 and spiropyrimidinetriones. 14 …”

Section: Introductionmentioning

confidence: 99%

Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

et al. 2018

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There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure–activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds 6o and 6v showed improved MIC90 values against Escherichia coli (0.5–1 μg/mL) and Acinetobacter baumannii (8–16 μg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of E. coli.

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Section: Introductionmentioning

confidence: 99%

Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

et al. 2018

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“…In the design of our isothiazolone–nitroxide hybrids, we considered the various positions surrounding the isothiazolone core for nitroxide functionalization. However, functionalization at the nitrogen atom, to generate N -substituted isothiazolones, is one of the most common sites for the generation of biologically active isothiazolones. − A widely used method to produce N -substituted isothiazolones is through chlorine-induced oxidative cyclization of 3,3′-dithiodipropioamides (Scheme ), a method documented by Szamborski and co-workers in 1971 . Utilizing this methodology, we sought to produce nitroxide-functionalized isothiazolones.…”

Section: Results and Discussionmentioning

confidence: 99%

Isothiazolone–Nitroxide Hybrids with Activity against Antibiotic-Resistant Staphylococcus aureus Biofilms

et al. 2022

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Isothiazolones are widely used as biocides in industrial processing systems and personal care products, but their use to treat infections in humans has been hampered by their inherent cytotoxicity. Herein, we report a strategy to alleviate isothiazolone toxicity and improve antibacterial and antibiofilm potency by functionalization with a nitroxide moiety. Isothiazolone–nitroxide hybrids 6 and 22 were prepared over three steps in moderate yields (58 and 36%, respectively) from (Z)-3-(benzylsulfanyl)-propenoic acid. Hybrid 22 displayed better activity (minimum inhibitory concentration (MIC) = 35 μM) than the widely used methylisothiazolinone (MIT 1, MIC = 280 μM) against methicillin-susceptible Staphylococcus aureus (MSSA). Hybrid 22 was even more active against drug-resistant strains, such as vancomycin-resistant Staphylococcus aureus (VRSA, MIC = 8.75 μM) over MIT 1 (MIC = 280 μM). The enhanced antibacterial activity of hybrid 22 over MIT 1 was retained against established MSSA and VRSA biofilms, with minimum biofilm eradication concentration (MBEC) values of 35 and 70 μM, respectively, for 22 (the MBEC value for MIT 1 against both strains was ≥280 μM). No toxicity was observed in human epithelial T24 cells treated with hybrid 22 in concentrations up to 560 μM using a lactate dehydrogenase assay.

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“…Here, an even more important finding of these studies is the high potency of the compounds 1 – 8 against Gram-negative ESKAPE bacteria, which clearly distinguishes these selenazolinium compounds from ebselen and places them on par with the best anti-ESKAPE agents found recently, such as isothiazolone [ 40 ] or bis-cyclic guanidine compounds [ 41 ]. The results obtained here with 14 different Gram-negative strains evidently confirm the promising properties of the entire group of both, the 3-bromo-selenazolopyridinium chlorides ( 1 – 7 ) and 3-bromo-2-(1-hydroxycyclohexyl)[1,2]selenazolo[2,3- b ]thiazolinium chloride ( 8 ), against both types of ESKAPE strains, with special accent on the selenazolopyridinium compounds 1 and 3 ( Figure 1 , Table 2 and Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

Selenazolinium Salts as “Small Molecule Catalysts” with High Potency against ESKAPE Bacterial Pathogens

et al. 2017

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In view of the pressing need to identify new antibacterial agents able to combat multidrug-resistant bacteria, we investigated a series of fused selenazolinium derivatives (1–8) regarding their in vitro antimicrobial activities against 25 ESKAPE-pathogen strains. Ebselen was used as reference compound. Most of the selenocompounds demonstrated an excellent in vitro activity against all S. aureus strains, with activities comparable to or even exceeding the one of ebselen. In contrast to ebselen, some selenazolinium derivatives (1, 3, and 7) even displayed significant actions against all Gram-negative pathogens tested. The 3-bromo-2-(1-hydroxy-1-methylethyl)[1,2]selenazolo[2,3-a]pyridinium chloride (1) was particularly active (minimum inhibitory concentrations, MICs: 0.31–1.24 µg/mL for MRSA, and 0.31–2.48 µg/mL for Gram-negative bacteria) and devoid of any significant mutagenicity in the Ames assay. Our preliminary mechanistic studies in cell culture indicated that their mode of action is likely to be associated with an alteration of intracellular levels of glutathione and cysteine thiols of different proteins in the bacterial cells, hence supporting the idea that such compounds interact with the intracellular thiolstat. This alteration of pivotal cysteine residues is most likely the result of a direct or catalytic oxidative modification of such residues by the highly reactive selenium species (RSeS) employed.

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Discovery and structure–activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors

Cited by 10 publications

References 22 publications

Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

Isothiazolone–Nitroxide Hybrids with Activity against Antibiotic-Resistant Staphylococcus aureus Biofilms

Selenazolinium Salts as “Small Molecule Catalysts” with High Potency against ESKAPE Bacterial Pathogens

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