Design, synthesis and biological evaluation of novel pleuromutilin derivatives possessing 4-aminothiophenol linker as promising antibacterial agents

Chai, Fei; Wang, Jun; Zhou, Ke-Xin; Wang, Shou-Kai; Liu, Yahong; Jin, Zhen; Tang, You‐Zhi

doi:10.1016/j.bioorg.2022.105859

Cited by 8 publications

(6 citation statements)

References 30 publications

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“…Adduct ( 5 ) is the epicatechin–2–aminothiophenol and is the only molecule harboring an amino group. In agreement with our findings, recently, it was demonstrated that the introduction of amino-thiophenol as a linker in leuromutilin, a tricyclic diterpenoid natural product, allowed for obtaining a new type of antibiotic with a powerful in vitro and in vivo effect against S. aureus MSRA and E. coli (ATCC 25922) [ 52 , 53 ]. Therefore, these adducts could be used in the future as a new scaffold directed against this pathogen.…”

Section: Resultssupporting

confidence: 91%

Synthesis and Isolation of Phenol- and Thiol-Derived Epicatechin Adducts Prepared from Avocado Peel Procyanidins Using Centrifugal Partition Chromatography and the Evaluation of Their Antimicrobial and Antioxidant Activity

Berrios-Henríquez,

Venegas-Toloza,

Reyes-Fuentes

et al. 2024

Molecules

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Polyphenols from agro-food waste represent a valuable source of bioactive molecules that can be recovered to be used for their functional properties. Another option is to use them as starting material to generate molecules with new and better properties through semi-synthesis. A proanthocyanidin-rich (PACs) extract from avocado peels was used to prepare several semi-synthetic derivatives of epicatechin by acid cleavage in the presence of phenol and thiol nucleophiles. The adducts formed by this reaction were successfully purified using one-step centrifugal partition chromatography (CPC) and identified by chromatographic and spectroscopic methods. The nine derivatives showed a concentration-dependent free radical scavenging activity in the DPPH assay. All compounds were also tested against a panel of pathogenic bacterial strains formed by Listeria monocytogenes (ATCC 7644 and 19115), Staphylococcus aureus (ATCC 9144), Escherichia coli (ATCC 11775 and 25922), and Salmonella enterica (ATCC 13076). In addition, adducts were tested against two no-pathogenic strains, Limosilactobacillus fermentum UCO-979C and Lacticaseibacillus rhamnosus UCO-25A. Overall, thiol-derived adducts displayed antimicrobial properties and, in some specific cases, inhibited biofilm formation, particularly in Listeria monocytogenes (ATCC 7644). Interestingly, phenolic adducts were inactive against all the strains and could not inhibit its biofilm formation. Moreover, depending on the structure, in specific cases, biofilm formation was strongly promoted. These findings contribute to demonstrating that CPC is a powerful tool to isolate new semi-synthetic molecules using avocado peels as starting material for PACc extraction. These compounds represent new lead molecules with antioxidant and antimicrobial activity.

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Section: Resultssupporting

confidence: 91%

Synthesis and Isolation of Phenol- and Thiol-Derived Epicatechin Adducts Prepared from Avocado Peel Procyanidins Using Centrifugal Partition Chromatography and the Evaluation of Their Antimicrobial and Antioxidant Activity

Berrios-Henríquez,

Venegas-Toloza,

Reyes-Fuentes

et al. 2024

Molecules

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“…The microbroth dilution method was used to evaluate the in vitro antibacterial activities of all the synthesized compounds [44,45]. Gram-positive bacteria S. aureus and Gram-negative bacteria E. coli were selected as the tested organisms.…”

Section: Antibacterial Activity Evaluation In Vitromentioning

confidence: 99%

Synthesis and Antibacterial Activity of Novel Triazolo[4,3-a]pyrazine Derivatives

Hu,

Dong,

et al. 2023

Molecules

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Infectious diseases pose a major challenge to human health, and there is an urgent need to develop new antimicrobial agents with excellent antibacterial activity. A series of novel triazolo[4,3-a]pyrazine derivatives were synthesized and their structures were characterized using various techniques, such as melting point, 1H and 13C nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. All the synthesized compounds were evaluated for in vitro antibacterial activity using the microbroth dilution method. Among all the tested compounds, some showed moderate to good antibacterial activities against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli strains. In particular, compound 2e exhibited superior antibacterial activities (MICs: 32 μg/mL against Staphylococcus aureus and 16 μg/mL against Escherichia coli), which was comparable to the first-line antibacterial agent ampicillin. In addition, the structure–activity relationship of the triazolo[4,3-a]pyrazine derivatives was preliminarily investigated.

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“…The natural product pleuromutilin ( 1 , Figure ), discovered in 1951, , is an attractive foundation for new antibiotics. This is emphasized by the more than 40 pleuromutilin medicinal chemistry and total synthesis articles published within the field over the last 5 years, with some reporting very potent activity and high clinical potential, − and in some cases also by employing novel and unique strategies. ,,,,,− …”

Section: Introductionmentioning

confidence: 99%

Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate

Heidtmann,

Fejer,

Stærk

et al. 2024

J. Med. Chem.

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Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate 16, based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hitoptimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate 16 was extensively evaluated for its in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of 16 proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The in vivo efficacy was evaluated in mice, systemically infected with Staphylococcus aureus, where 16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead 16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.

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Design, synthesis and biological evaluation of novel pleuromutilin derivatives possessing 4-aminothiophenol linker as promising antibacterial agents

Cited by 8 publications

References 30 publications

Synthesis and Isolation of Phenol- and Thiol-Derived Epicatechin Adducts Prepared from Avocado Peel Procyanidins Using Centrifugal Partition Chromatography and the Evaluation of Their Antimicrobial and Antioxidant Activity

Synthesis and Isolation of Phenol- and Thiol-Derived Epicatechin Adducts Prepared from Avocado Peel Procyanidins Using Centrifugal Partition Chromatography and the Evaluation of Their Antimicrobial and Antioxidant Activity

Synthesis and Antibacterial Activity of Novel Triazolo[4,3-a]pyrazine Derivatives

Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate

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