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

doi:10.1016/j.bmc.2020.115439

Back

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

Journal article

Open access

Peer reviewed

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 and Robert J. Kerns

Bioorganic & medicinal chemistry, Vol.28(10), pp.115439-115439

05/15/2020

DOI: 10.1016/j.bmc.2020.115439

PMCID: PMC7331940

PMID: 32234278

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/7331940View

Open Access

Abstract

To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. [Display omitted] 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.

DNA gyrase

Fluoroquinolones

Quinazolinediones

Topoisomerase

Details

Title: Subtitle: Identification of an ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate as a catalytic inhibitor of DNA gyrase
Creators: Arturo L. Aguirre - University of Iowa
Pratik R. Chheda - University of Iowa
Sarah R.C. Lentz - University of Minnesota
Hailey A. Held - University of Minnesota
Natalie P. Groves - University of Minnesota
Hiroshi Hiasa - University of Minnesota
Robert J. Kerns - Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave., S321 Pharmacy Building, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry, Vol.28(10), pp.115439-115439
DOI: 10.1016/j.bmc.2020.115439
PMID: 32234278
PMCID: PMC7331940
NLM abbreviation: Bioorg Med Chem
ISSN: 0968-0896
eISSN: 1464-3391
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 AI87671; DOI: 10.13039/100012675, name: University of Iowa Center for Biocatalysis and Bioprocessing; name: Predoctoral Training Program in Biotechnology, award: T32 GM008365
Language: English
Date published: 05/15/2020
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984366038902771

Metrics

15 Record Views

14 Times Cited - Web of Science

See more details