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Design and synthesis of new N-thioacylated ciprofloxacin derivatives as urease inhibitors with potential antibacterial activity.

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Title: Design and synthesis of new N-thioacylated ciprofloxacin derivatives as urease inhibitors with potential antibacterial activity.
Authors: Pedrood, Keyvan, Azizian, Homa, Montazer, Mohammad Nazari, Moazzam, Ali, Asadi, Mehdi, Montazeri, Hamed, Biglar, Mahmood, Zamani, Mozhdeh, Larijani, Bagher, Zomorodian, Kamiar, Mohammadi-Khanaposhtani, Maryam, Irajie, Cambyz, Amanlou, Massoud, Iraji, Aida, Mahdavi, Mohammad
Source: Scientific Reports; 8/15/2022, Vol. 12 Issue 1, p1-17, 17p
Subject Terms: Urease, Antibacterial agents, Escherichia coli, Ciprofloxacin, Drug standards, Gram-negative bacteria
Abstract: A new series of N-thioacylated ciprofloxacin 3a–n were designed and synthesized based on Willgerodt–Kindler reaction. The results of in vitro urease inhibitory assay indicated that almost all the synthesized compounds 3a–n (IC50 = 2.05 ± 0.03–32.49 ± 0.32 μM) were more potent than standard inhibitors, hydroxyurea (IC50 = 100 ± 2.5 μM) and thiourea (IC50 = 23 ± 0.84 μM). The study of antibacterial activity against Gram-positive species (S. aureus and S. epidermidis) revealed that the majority of compounds were more active than ciprofloxacin as the standard drug, and 3h derivative bearing 3-fluoro group had the same effect as ciprofloxacin against Gram-negative bacteria (P. aeruginosa and E. coli). Based on molecular dynamic simulations, compound 3n exhibited pronounced interactions with the critical residues of the urease active site and mobile flap pocket so that the quinolone ring coordinated toward the metal bi-nickel center and the essential residues at the flap site like His593, His594, and Arg609. These interactions caused blocking the active site and stabilized the movement of the mobile flap at the entrance of the active site channel, which significantly reduced the catalytic activity of urease. Noteworthy, 3n also exhibited IC50 values of 5.59 ± 2.38 and 5.72 ± 1.312 µg/ml to inhibit urease enzyme against C. neoformans and P. vulgaris in the ureolytic assay. [ABSTRACT FROM AUTHOR]
Copyright of Scientific Reports is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  – Url: https://dx.doi.org/doi:10.1038/s41598-022-17993-4
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  Label: Title
  Group: Ti
  Data: Design and synthesis of new N-thioacylated ciprofloxacin derivatives as urease inhibitors with potential antibacterial activity.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Pedrood%2C+Keyvan%22">Pedrood, Keyvan</searchLink><br /><searchLink fieldCode="AR" term="%22Azizian%2C+Homa%22">Azizian, Homa</searchLink><br /><searchLink fieldCode="AR" term="%22Montazer%2C+Mohammad+Nazari%22">Montazer, Mohammad Nazari</searchLink><br /><searchLink fieldCode="AR" term="%22Moazzam%2C+Ali%22">Moazzam, Ali</searchLink><br /><searchLink fieldCode="AR" term="%22Asadi%2C+Mehdi%22">Asadi, Mehdi</searchLink><br /><searchLink fieldCode="AR" term="%22Montazeri%2C+Hamed%22">Montazeri, Hamed</searchLink><br /><searchLink fieldCode="AR" term="%22Biglar%2C+Mahmood%22">Biglar, Mahmood</searchLink><br /><searchLink fieldCode="AR" term="%22Zamani%2C+Mozhdeh%22">Zamani, Mozhdeh</searchLink><br /><searchLink fieldCode="AR" term="%22Larijani%2C+Bagher%22">Larijani, Bagher</searchLink><br /><searchLink fieldCode="AR" term="%22Zomorodian%2C+Kamiar%22">Zomorodian, Kamiar</searchLink><br /><searchLink fieldCode="AR" term="%22Mohammadi-Khanaposhtani%2C+Maryam%22">Mohammadi-Khanaposhtani, Maryam</searchLink><br /><searchLink fieldCode="AR" term="%22Irajie%2C+Cambyz%22">Irajie, Cambyz</searchLink><br /><searchLink fieldCode="AR" term="%22Amanlou%2C+Massoud%22">Amanlou, Massoud</searchLink><br /><searchLink fieldCode="AR" term="%22Iraji%2C+Aida%22">Iraji, Aida</searchLink><br /><searchLink fieldCode="AR" term="%22Mahdavi%2C+Mohammad%22">Mahdavi, Mohammad</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: Scientific Reports; 8/15/2022, Vol. 12 Issue 1, p1-17, 17p
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Urease%22">Urease</searchLink><br /><searchLink fieldCode="DE" term="%22Antibacterial+agents%22">Antibacterial agents</searchLink><br /><searchLink fieldCode="DE" term="%22Escherichia+coli%22">Escherichia coli</searchLink><br /><searchLink fieldCode="DE" term="%22Ciprofloxacin%22">Ciprofloxacin</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+standards%22">Drug standards</searchLink><br /><searchLink fieldCode="DE" term="%22Gram-negative+bacteria%22">Gram-negative bacteria</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: A new series of N-thioacylated ciprofloxacin 3a–n were designed and synthesized based on Willgerodt–Kindler reaction. The results of in vitro urease inhibitory assay indicated that almost all the synthesized compounds 3a–n (IC<subscript>50</subscript> = 2.05 ± 0.03–32.49 ± 0.32 μM) were more potent than standard inhibitors, hydroxyurea (IC<subscript>50</subscript> = 100 ± 2.5 μM) and thiourea (IC<subscript>50</subscript> = 23 ± 0.84 μM). The study of antibacterial activity against Gram-positive species (S. aureus and S. epidermidis) revealed that the majority of compounds were more active than ciprofloxacin as the standard drug, and 3h derivative bearing 3-fluoro group had the same effect as ciprofloxacin against Gram-negative bacteria (P. aeruginosa and E. coli). Based on molecular dynamic simulations, compound 3n exhibited pronounced interactions with the critical residues of the urease active site and mobile flap pocket so that the quinolone ring coordinated toward the metal bi-nickel center and the essential residues at the flap site like His593, His594, and Arg609. These interactions caused blocking the active site and stabilized the movement of the mobile flap at the entrance of the active site channel, which significantly reduced the catalytic activity of urease. Noteworthy, 3n also exhibited IC<subscript>50</subscript> values of 5.59 ± 2.38 and 5.72 ± 1.312 µg/ml to inhibit urease enzyme against C. neoformans and P. vulgaris in the ureolytic assay. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Scientific Reports is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1038/s41598-022-17993-4
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      – Code: eng
        Text: English
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      – SubjectFull: Urease
        Type: general
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      – SubjectFull: Escherichia coli
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              Text: 8/15/2022
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