Discovery of benzopyridone cyanoacetates as new type of potential broad-spectrum antibacterial candidates

Zhang, Jing; Tan, Yi-Min; Li, Shu-Rui; Battini, Narsaiah; Zhang, Shao-Lin; Lin, Jian-Mei; Zhou, Cheng-He

doi:10.1016/j.ejmech.2023.116107

Cited by 10 publications

(3 citation statements)

References 92 publications

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“…To further confirm the interaction mode of nitrofuryl HN 4a with DNA, acridine orange (AO) as a cationic dye was also applied as a spectral probe in this work referring to the reported literature . As shown in Figure B, the fluorescence intensity decreased obviously at 537 nm with the amount of the equivalent of nitrofuryl HN 4a , which suggested that nitrofuryl HN 4a could embed into DNA by replacing AO in the DNA–AO complex.…”

Section: Resultsmentioning

confidence: 99%

A Unique Hybridization Route to Access Hydrazylnaphthalimidols as Novel Structural Scaffolds of Multitargeting Broad-Spectrum Antifungal Candidates

Wang,

Zhang,

Gopala

et al. 2024

J. Med. Chem.

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This study developed a class of novel structural antifungal hydrazylnaphthalimidols (HNs) with multitargeting broad-spectrum potential via multicomponent hybridization to confront increasingly severe fungal invasion. Some prepared HNs exhibited considerable antifungal potency; especially nitrofuryl HN 4a (MIC = 0.001 mM) exhibited a potent antifungal activity against Candida albicans, which is 13-fold higher than that of fluconazole. Furthermore, nitrofuryl HN 4a displayed low cytotoxicity, hemolysis and resistance, as well as a rapid fungicidal efficacy. Preliminary mechanistic investigations revealed that nitrofuryl HN 4a could inhibit lactate dehydrogenase to decrease metabolic activity and promote the accumulation of reactive oxygen species, leading to oxidative stress. Moreover, nitrofuryl HN 4a did not exhibit membrane-targeting ability; it could embed into DNA to block DNA replication but could not cleave DNA. These findings implied that HNs are promising as novel structural scaffolds of potential multitargeting broad-spectrum antifungal candidates for treating fungal infection.

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Section: Resultsmentioning

confidence: 99%

A Unique Hybridization Route to Access Hydrazylnaphthalimidols as Novel Structural Scaffolds of Multitargeting Broad-Spectrum Antifungal Candidates

Wang,

Zhang,

Gopala

et al. 2024

J. Med. Chem.

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“…Cannabidiols have been very recently published as broad-spectrum anti-bacterial agents, and their lead compound acted as a bactericidal agent through a membrane-targeting mechanism with a low resistance frequency ( Fang et al., 2024 ). Benzopyridone cyanoacetates have been reported as a new type of broad-spectrum anti-bacterial with low MIC values against several tested strains, bactericidal mode of action, and a low resistant trend ( Zhang et al., 2024 ). The anti-bacterial compound MA220607 was published as dual-targeting inhibitor, facilitating FtsZ polymerization and perturbing bacterial membranes.…”

Section: Evaluating Anti-bacterial Activity Of Novel Compoundsmentioning

confidence: 99%

Evaluation of novel compounds as anti-bacterial or anti-virulence agents

Filipić,

Ušjak,

Rambaher

et al. 2024

Front. Cell. Infect. Microbiol.

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Antimicrobial resistance is a global threat, leading to an alarming increase in the prevalence of bacterial infections that can no longer be treated with available antibiotics. The World Health Organization estimates that by 2050 up to 10 million deaths per year could be associated with antimicrobial resistance, which would equal the annual number of cancer deaths worldwide. To overcome this emerging crisis, novel anti-bacterial compounds are urgently needed. There are two possible approaches in the fight against bacterial infections: a) targeting structures within bacterial cells, similar to existing antibiotics; and/or b) targeting virulence factors rather than bacterial growth. Here, for the first time, we provide a comprehensive overview of the key steps in the evaluation of potential new anti-bacterial and/or anti-virulence compounds. The methods described in this review include: a) in silico methods for the evaluation of novel compounds; b) anti-bacterial assays (MIC, MBC, Time-kill); b) anti-virulence assays (anti-biofilm, anti-quorum sensing, anti-adhesion); and c) evaluation of safety aspects (cytotoxicity assay and Ames test). Overall, we provide a detailed description of the methods that are an essential tool for chemists, computational chemists, microbiologists, and toxicologists in the evaluation of potential novel antimicrobial compounds. These methods are cost-effective and have high predictive value. They are widely used in preclinical studies to identify new molecular candidates, for further investigation in animal and human trials.

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“…Almost all positions in the quinolone core can be modified, and hybridization with various antibacterial functional fragments is extensively studied for multichannel development of antibacterial quinolones. − The prevalence of cyano-containing drugs underscores the feasibility of using the cyano functional group as a short and polar triple bond, which facilitates their incorporation into protein-binding sites via various noncovalent interactions. − Moreover, the cyano group can improve the pharmacokinetic properties of small molecule drugs and can be metabolized unchangeably by organisms without the release of cyanides. Thus, it is prescribed for excavation of diverse drugs, − including pradofloxacin, which features an 8-cyano group and is suitable as a broad-spectrum veterinary antibacterial drug and antifungal azoxystrobin .…”

Section: Introductionmentioning

confidence: 99%

Cyanomethylquinolones as a New Class of Potential Multitargeting Broad-Spectrum Antibacterial Agents

Tan,

Zhang,

Wei

et al. 2024

J. Med. Chem.

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This work identified a class of cyanomethylquinolones (CQs) and their carboxyl analogues as potential multitargeting antibacterial candidates. Most of the prepared compounds showed high antibacterial activities against most of the tested bacteria, exhibiting lower MIC values (0.125−2 μg/mL) than those of clinical norfloxacin, ciprofloxacin, and clinafloxacin. The low hemolysis, drug resistance, and cytotoxicity, as well as good predictive pharmacokinetics of active CQs and carboxyl analogues revealed their development potential. Furthermore, they could eradicate the established biofilm, facilitating bacterial exposure to these antibacterial candidates. These active compounds could induce bacterial death through multitargeting effects, including intercalating into DNA, up-regulating reactive oxygen species, damaging membranes directly, and impeding metabolism. Moreover, the highly active cyclopropyl CQ 15 exhibited more effective in vivo anti-MRSA potency than ciprofloxacin. These findings highlight the potential of CQs and their carboxyl analogues as multitargeting broad-spectrum antibacterial candidates for treating intractable bacterial infections.

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Discovery of benzopyridone cyanoacetates as new type of potential broad-spectrum antibacterial candidates

Cited by 10 publications

References 92 publications

A Unique Hybridization Route to Access Hydrazylnaphthalimidols as Novel Structural Scaffolds of Multitargeting Broad-Spectrum Antifungal Candidates

A Unique Hybridization Route to Access Hydrazylnaphthalimidols as Novel Structural Scaffolds of Multitargeting Broad-Spectrum Antifungal Candidates

Evaluation of novel compounds as anti-bacterial or anti-virulence agents

Cyanomethylquinolones as a New Class of Potential Multitargeting Broad-Spectrum Antibacterial Agents

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