Identification of an ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate as a catalytic inhibitor of DNA gyrase

Arturo L. Aguirre, Pratik R. Chheda, Sarah R.C. Lentz, Hailey A. Held, Natalie P. Groves, Hiroshi Hiasa, Robert J. Kerns

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7 Scopus citations


Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections and target bacterial type-II topoisomerases (DNA gyrase and topoisomerase IV). Fluoroquinolones, however potent, are susceptible to bacterial resistance with prolonged use, which limits their use in the clinic. Quinazoline-2,4-diones also target bacterial type-II topoisomerases and are not susceptible to bacterial resistance similar to fluoroquinolones, however, their potency pales in comparison to fluoroquinolones. To meet the increasing demand for antibacterial development, nine modified quinazoline-2,4-diones were developed to probe quinazoline-2,4-dione structure modification for possible new binding contacts with the bacterial type-II topoisomerase, DNA gyrase. Evaluation of compounds for inhibition of the supercoiling activity of DNA gyrase revealed a novel ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate derivative as a modest inhibitor of DNA gyrase, having an IC50 of 3.5 μM. However, this ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate does not trap the catalytic intermediate like fluoroquinolones or typical quinazoline-2,4-diones do. Thus, the ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate derivative discovered in this work acts as a catalytic inhibitor of DNA gyrase and therefore represents a new structural type of catalytic inhibitor of DNA gyrase.

Original languageEnglish (US)
Article number115439
JournalBioorganic and Medicinal Chemistry
Issue number10
StatePublished - May 15 2020

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) Research Grant R01 AI87671 to RJK. Arturo Aguirre and Pratik Chheda acknowledge training program support from the University of Iowa Center for Biocatalysis and Bioprocessing and the NIH-sponsored Predoctoral Training Program in Biotechnology ( T32 GM008365 ).

Publisher Copyright:
© 2020 Elsevier Ltd


  • DNA gyrase
  • Fluoroquinolones
  • Quinazolinediones
  • Topoisomerase


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