Pyrimidine-conjugated fluoroquinolones as new potential broad-spectrum antibacterial agents

Tan, Yi-Min; Li, Di; Li, Fenfen; Ansari, Mohammad Fawad; Fang, Bo; Zhou, Cheng‐He

doi:10.1016/j.bmcl.2022.128885

Cited by 35 publications

(10 citation statements)

References 68 publications

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“…The binding of small molecules and DNA is of great significance for the rational design and construction of new and efficient drugs targeting DNA. , Many studies have also pointed out DNA as the direct binding species of antibacterial quinolones. − This study explored the possible interaction mechanism between 3-(aminothiazolyl)quinolone 17a and DNA via ultraviolet–visible spectroscopy and fluorescence spectrometry.…”

Section: Results and Discussionmentioning

confidence: 99%

New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential

Zhang

Battini

et al. 2023

J. Agric. Food Chem.

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New antibacterial 3-(aminothiazolyl)quinolones (ATQs) were designed and efficiently synthesized to counteract the growing multidrug resistance in animal husbandry. Bioactive assays manifested that N,N-dicyclohexylaminocarbonyl ATQ 10e and methyl ATQ 17a, respectively, showed better antibacterial behavior against Staphylococcus aureus ATCC 29213 and Pseudomonas aeruginosa than reference drug norfloxacin. Notably, highly active ATQ 17a with low hemolysis, negligible mammalian cytotoxicity, and good pharmacokinetic properties displayed low trends to induce resistance and synergistic combinations with norfloxacin. Preliminary mechanism exploration implied that representative ATQ 17a could inhibit the formation of biofilms and destroy bacterial membrane integrity, further binding to intracellular DNA and DNA gyrase to hinder bacterial DNA replication. ATQ 17a could also induce the production of excess reactive oxygen species and reduce bacterial metabolism to accelerate bacterial death. These results provided a promise for 3-(aminothiazolyl)quinolones as new potential multitargeting antibacterial agents to treat bacterial infection of animals.

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Section: Results and Discussionmentioning

confidence: 99%

New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential

Zhang

Battini

et al. 2023

J. Agric. Food Chem.

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“…ADMET screening rules are an indispensable part of modern drug development [ 43 , 44 , 45 ]. They are not only an important experimental specification for estimating the safety and effectiveness of drugs in healthy populations but also an important avenue for assessing the development potential of drugs in the future.…”

Section: Resultsmentioning

confidence: 99%

Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a

et al. 2023

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Bacterial infections caused by methicillin-resistant Staphylococcus aureus have seriously threatened public health. There is an urgent need to propose an existing regimen to overcome multidrug resistance of MRSA. A unique class of novel anti-MRSA thiazolylketenyl quinazolinones (TQs) and their analogs were developed. Some synthesized compounds showed good bacteriostatic potency. Especially TQ 4 was found to exhibit excellent inhibition against MRSA with a low MIC of 0.5 μg/mL, which was 8-fold more effective than norfloxacin. The combination of TQ 4 with cefdinir showed stronger antibacterial potency. Further investigation revealed that TQ 4, with low hemolytic toxicity and low drug resistance, was not only able to inhibit biofilm formation but also could reduce MRSA metabolic activity and showed good drug-likeness. Mechanistic explorations revealed that TQ 4 could cause leakage of proteins by disrupting membrane integrity and block DNA replication by intercalated DNA. Furthermore, the synergistic antibacterial effect with cefdinir might be attributed to TQ 4 with the ability to induce PBP2a allosteric regulation of MRSA and further trigger the opening of the active site to promote the binding of cefdinir to the active site, thus inhibiting the expression of PBP2a, thereby overcoming MRSA resistance and significantly enhancing the anti-MRSA activity of cefdinir. A new strategy provided by these findings was that TQ 4, possessing both excellent anti-MRSA activity and allosteric effect of PBP2a, merited further development as a novel class of antibacterial agents to overcome increasingly severe MRSA infections.

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“…The six-membered heterocyclic pyrimidine with two nitrogen atoms is widely present in a lot of biomolecules like DNA and clinical drugs such as antibacterial sulfonamides in which pyrimidine ring plays a positive role in exerting biological activities. − It is revealed that many antimicrobial pyrimidine derivatives could bind to DNA via weak interactions to block bacterial DNA replication and thus reduce the viability of microorganisms. − The incorporation of pyrimidines and versatile functional fragments has been extensively studied to discover new pyrimidine-based antimicrobial agents. − Especially, the pyrimidine-hybridized azoles like pyrazole and benzothiazole were reported to exhibit admirable antimicrobial efficacy. − It is well known that the aromatic heterocyclic azoles as drugs are exerting positive impact in treating a variety of diseases especially microbial infections; it has been found that the various biological effects are derived from the effective interactions via noncovalent bonds between the electron-rich aromatic azole ring and the biological targets. , Therein, imidazole as a significant moiety in endogenous biomolecules arouses great attention in antimicrobial medicinal chemistry. , Plenty of imidazole-based drugs like metronidazole, ornidazole, morinidazole, and so on, make great contribution to the treatment of clinical microbial infections. , Our previous work showed that the combination of imidazole and pyrimidines produced some potential multitargeting antibacterial molecules, , manifesting that such an incorporation was a promising strategy anticipated to the discovery of diverse antibacterial pyrimidine derivatives. In this content, imidazolylpyrimidinediols and their analogues as novel structural scaffolds were constructed for the first time, which might be a new lenitive for the abominable drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Azolylpyrimidinediols as Novel Structural Scaffolds of DNA-Groove Binders against Intractable Acinetobacter baumannii

Tan

Wang

et al. 2023

J. Med. Chem.

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A unique class of antibacterial azolylpyrimidinediols (APDs) and their analogues were developed. Some synthesized compounds showed excellent bacteriostatic potency; especially, triazolylpyrimidinediol (triazolyl PD) 7a exhibited good anti-Acinetobacter baumannii potential with a low MIC of 0.002 mmol/ L. Triazolyl PD 7a with inconspicuous cytotoxicity and hemolytic activity could eradicate the established biofilm, showed low resistance, and exhibited favorable drug-likeness. Mechanistic explorations revealed that compound 7a without membrane-targeting ability could decrease metabolic activity, interact with DNA through groove binding action to block DNA replication rather than intercalate into and cleave DNA, and thus inhibit bacterial growth. Further computations displayed that the low E HOMO and large energy gap might help triazolyl PD 7a binding to biological targets more easily. Moreover, compound 7a gave appreciable in vivo pharmacokinetic properties and pharmacodynamics. These findings of azolylpyrimidinediols as novel structural scaffolds of DNA-groove binders might imply a large promise for the treatments of Acinetobacter baumannii infection.

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Pyrimidine-conjugated fluoroquinolones as new potential broad-spectrum antibacterial agents

Cited by 35 publications

References 68 publications

New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential

New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential

Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a

Azolylpyrimidinediols as Novel Structural Scaffolds of DNA-Groove Binders against Intractable Acinetobacter baumannii

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