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Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors
ID
Jakopin, Žiga
(
Author
),
ID
Ilaš, Janez
(
Author
),
ID
Barančokova, Michaela
(
Author
),
ID
Brvar, Matjaž
(
Author
),
ID
Tammela, Päivi
(
Author
),
ID
Sollner Dolenc, Marija
(
Author
),
ID
Tomašič, Tihomir
(
Author
),
ID
Kikelj, Danijel
(
Author
)
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https://www.sciencedirect.com/science/article/pii/S0223523417301198
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Abstract
DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 mM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Grampositive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 mM. OuDNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 mM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Grampositive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 mM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IVr study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV.
Language:
English
Keywords:
1
,
2
,
4-oxadiazoles
,
DNA gyrase inhibition
,
topoisomerase IV inhibition
,
antibacterial screening
,
computer-aided drug design
Work type:
Scientific work
Typology:
1.01 - Original Scientific Article
Organization:
FFA - Faculty of Pharmacy
Publication status:
Published
Publication version:
Author Accepted Manuscript
Year:
2017
Number of pages:
Str. 171-184
Numbering:
Vol. 130
PID:
20.500.12556/RUL-106640
UDC:
615.4:54
ISSN on article:
0223-5234
DOI:
10.1016/j.ejmech.2017.02.046
COBISS.SI-ID:
4292465
Publication date in RUL:
09.03.2019
Views:
1485
Downloads:
957
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Record is a part of a journal
Title:
European journal of medicinal chemistry
Shortened title:
Eur. j. med. chem.
Publisher:
Elsevier
ISSN:
0223-5234
COBISS.SI-ID:
25429760
Licences
License:
CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Link:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Description:
The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.
Licensing start date:
09.03.2019
Projects
Funder:
EC - European Commission
Funding programme:
H2020
Project number:
642620
Name:
Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets
Acronym:
INTEGRATE
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