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Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors
ID Jakopin, Žiga (Avtor), ID Ilaš, Janez (Avtor), ID Barančokova, Michaela (Avtor), ID Brvar, Matjaž (Avtor), ID Tammela, Päivi (Avtor), ID Sollner Dolenc, Marija (Avtor), ID Tomašič, Tihomir (Avtor), ID Kikelj, Danijel (Avtor)

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Izvleček
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inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market.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inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market.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.

Jezik:Angleški jezik
Ključne besede:1, 2, 4-oxadiazoles, DNA gyrase inhibition, topoisomerase IV inhibition, antibacterial screening, computer-aided drug design
Vrsta gradiva:Znanstveno delo
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Status publikacije:Objavljeno
Različica publikacije:Recenzirani rokopis
Leto izida:2017
Št. strani:Str. 171-184
Številčenje:Vol. 130
PID:20.500.12556/RUL-106640 Povezava se odpre v novem oknu
UDK:615.4:54
ISSN pri članku:0223-5234
DOI:10.1016/j.ejmech.2017.02.046 Povezava se odpre v novem oknu
COBISS.SI-ID:4292465 Povezava se odpre v novem oknu
Datum objave v RUL:09.03.2019
Število ogledov:1278
Število prenosov:925
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
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Gradivo je del revije

Naslov:European journal of medicinal chemistry
Skrajšan naslov:Eur. j. med. chem.
Založnik:Elsevier
ISSN:0223-5234
COBISS.SI-ID:25429760 Povezava se odpre v novem oknu

Licence

Licenca:CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
Povezava:http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
Opis:Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.
Začetek licenciranja:09.03.2019

Projekti

Financer:EC - European Commission
Program financ.:H2020
Številka projekta:642620
Naslov:Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets
Akronim:INTEGRATE

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