Identification of an ethyl 5, 6-dihydropyrazolo[1, 5-c]quinazoline-1-carboxylate as a catalytic inhibitor of DNA gyrase. Issue 10 (15th May 2020)

• Record Type: Journal Article
• Authors: Aguirre, Arturo L.; Chheda, Pratik R.; Lentz, Sarah R.C.; Held, Hailey A.; Groves, Natalie P.; Hiasa, Hiroshi; Kerns, Robert J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 10(2020)
• Publication Date: 2020-05-15
• Subjects: DNA gyrase -- Quinazolinediones -- Fluoroquinolones -- Topoisomerase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115439
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. Abstract: 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.