Thiazolidine-2,4-dione-linked ciprofloxacin derivatives with broad-spectrum antibacterial, MRSA and topoisomerase inhibitory activities

Aziz, Hossameldin A.; El‐Saghier, Ahmed M. M.; Badr, Mohamed; Abuo‐Rahma, Gamal El‐Din A.; Shoman, Mai E.

doi:10.1007/s11030-021-10302-7

Cited by 22 publications

(8 citation statements)

References 49 publications

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“…6 ), indicating AOH effectively blocked the unwinding activities of the above four topoisomerases. As topoisomerases are closely related to bacterial DNA replication and cell division ( 44 ), we speculate that topoisomerase might be one of the key action targets of AOH against MRSA.…”

Section: Resultsmentioning

confidence: 98%

Antibacterial insights into alternariol and its derivative alternariol monomethyl ether produced by a marine fungus

Li,

Su,

Sun

et al. 2024

Appl Environ Microbiol

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Alternaria alternata FB1 is a marine fungus identified as a candidate for plastic degradation in our previous study. This fungus has been recently shown to produce secondary metabolites with significant antimicrobial activity against various pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and the notorious aquaculture pathogen Vibrio anguillarum . The antibacterial compounds were purified and identified as alternariol (AOH) and its derivative, alternariol monomethyl ether (AME). We found that AOH and AME primarily inhibited pathogenic bacteria (MRSA or V. anguillarum ) by disordering cell division and some other key physiological and biochemical processes. We further demonstrated that AOH could effectively inhibit the unwinding activity of MRSA topoisomerases, which are closely related to cell division and are the potential action target of AOH. The antibacterial activities of AOH and AME were verified by using zebrafish as the in vivo model. Notably, AOH and AME did not significantly affect the viability of normal human liver cells at concentrations that effectively inhibited MRSA or V. anguillarum . Finally, we developed the genetic operation system of A. alternata FB1 and blocked the biosynthesis of AME by knocking out omtI (encoding an O-methyl transferase), which facilitated A. alternata FB1 to only produce AOH. The development of this system in the marine fungus will accelerate the discovery of novel natural products and further bioactivity study. IMPORTANCE More and more scientific reports indicate that alternariol (AOH) and its derivative alternariol monomethyl ether (AME) exhibit antibacterial activities. However, limited exploration of their detailed antibacterial mechanisms has been performed. In the present study, the antibacterial mechanisms of AOH and AME produced by the marine fungus Alternaria alternata FB1 were disclosed in vitro and in vivo . Given their low toxicity on the normal human liver cell line under the concentrations exhibiting significant antibacterial activity against different pathogens, AOH and AME are proposed to be good candidates for developing promising antibiotics against methicillin-resistant Staphylococcus aureus and Vibrio anguillarum . We also succeeded in blocking the biosynthesis of AME, which facilitated us to easily obtain pure AOH. Moreover, based on our previous results, A. alternata FB1 was shown to enable polyethylene degradation.

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Section: Resultsmentioning

confidence: 98%

Antibacterial insights into alternariol and its derivative alternariol monomethyl ether produced by a marine fungus

Li,

Su,

Sun

et al. 2024

Appl Environ Microbiol

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“…The molecular docking tests demonstrated favorable interactions between the synthesized derivatives and the target protein, DNA gyrase enzyme (PDB: 2xct). 25 Fig. 4–9 exhibited the 2D and 3D representations of docking styles of target compounds 2, 3a–c and 4a,b with active site of DNA gyrase enzyme.…”

Section: Resultsmentioning

confidence: 99%

New quinazolin-2,4-dione derivatives incorporating acylthiourea, pyrazole and/or oxazole moieties as antibacterial agents via DNA gyrase inhibition

Ibrahim,

Hassan,

Mosallam

et al. 2024

RSC Adv.

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“…The desired intermediate pyrimidine derivatives 3a-i were prepared as reported by heating at reflux a mixture of ethyl cyanoacetate, thiourea, and the appropriate aromatic aldehyde in absolute ethanol in the presence of potassium carbonate as a base [40,41]. Ciprofloxacin derivative 4 was prepared by treating ciprofloxacin with bromoacetyl bromide in dichloromethane at 0 °C in the presence of TEA [42]. Alkylation of pyrimidine derivatives 3a-i with compound 4 were achieved in acetonitrile in the presence of TEA according to a reported procedure [43,44] to afford the target new compounds 5a-i.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and molecular docking of new N4-piperazinyl ciprofloxacin hybrids as antimicrobial DNA gyrase inhibitors

et al. 2022

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A series of N-4 piperazinyl ciprofloxacin derivatives as urea-tethered ciprofloxacin-chalcone hybrids 2a-j and thioacetyl-linked ciprofloxacin-pyrimidine hybrids 5a-i were synthesized. The target compounds were investigated for their antibacterial activity against S. aureus, P. aeruginosa, E. coli, and C. albicans strains, respectively. Ciprofloxacin derivatives 2a-j and 5a-i revealed broad antibacterial activity against either Gram positive or Gram negative strains, with MIC range of 0.06–42.23 µg/mL compared to ciprofloxacin with an MIC range of 0.15–3.25 µg/mL. Among the tested compounds, hybrids 2b, 2c, 5a, 5b, 5h, and 5i exhibited remarkable antibacterial activity with MIC range of 0.06–1.53 µg/mL against the tested bacterial strains. On the other hand, compounds 2c, 2e, 5c, and 5e showed comparable antifungal activity to ketoconazole against candida albicans with MIC range of 2.03–3.89 µg/mL and 2.6 µg/mL, respectively. Further investigations showed that some ciprofloxacin hybrids have inhibitory activity against DNA gyrase as potential molecular target compared to ciprofloxacin with IC50 range of 0.231 ± 0.01–7.592 ± 0.40 µM and 0.323 ± 0.02 µM, respectively. Docking studies of compounds 2b, 2c, 5b, 5c, 5e, 5h, and 5i on the active site of DNA gyrase (PDB: 2XCT) confirmed their ability to form stable complex with the target enzyme like that of ciprofloxacin. Graphical abstract

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Thiazolidine-2,4-dione-linked ciprofloxacin derivatives with broad-spectrum antibacterial, MRSA and topoisomerase inhibitory activities

Cited by 22 publications

References 49 publications

Antibacterial insights into alternariol and its derivative alternariol monomethyl ether produced by a marine fungus

Antibacterial insights into alternariol and its derivative alternariol monomethyl ether produced by a marine fungus

New quinazolin-2,4-dione derivatives incorporating acylthiourea, pyrazole and/or oxazole moieties as antibacterial agents via DNA gyrase inhibition

Synthesis and molecular docking of new N4-piperazinyl ciprofloxacin hybrids as antimicrobial DNA gyrase inhibitors

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