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Exploring the chemical space of benzothiazole-based DNA gyrase B inhibitorsSkok, Žiga, farmacevt ...We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl ... moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC50 = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 [micro]M), and efflux impaired E. coli strain (MIC = 0.78 [micro]M), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.Source: ACS Medicinal Chemistry Letters. - ISSN 1948-5875 (Vol. 11, iss. 12, 2020, str. 2433-2440)Type of material - article, component partPublish date - 2020Language - englishCOBISS.SI-ID - 32932099
Author
Skok, Žiga, farmacevt |
Barančokova, Michaela |
Benek, Ondřej |
Durante Cruz, Cristina |
Tammela, Päivi |
Tomašič, Tihomir |
Zidar, Nace |
Peterlin-Mašič, Lucija |
Zega, Anamarija |
Kikelj, Danijel |
Ilaš, Janez
Topics
Farmacevtska kemija |
DNA gyrase |
topoisomerase IV |
GyrB |
ParE |
antibacterial benzothiazole |
topoizomeraza IV |
giraza DNA |
antibakterijski benzotiazol |
inibitorji giraze B
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Author | Skok, Žiga, farmacevt ... |
Title | Exploring the chemical space of benzothiazole-based DNA gyrase B inhibitors |
Publication date | 2020-10-15 |
COBISS.SI-ID | 32932099 |
Publication version in repository | Publisher's version |
Publication licence | Unidentified |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
---|---|---|---|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Interdisciplinary Training Network for Validation of Gram-Negative Antibacterial Targets | INTEGRATE | 642620 |
European Commission |
Phenotypic biosensor-based HTS and mode of action analysis by metabolomics and transcriptomics for enhancing antimicrobial drug discovery against Gram-negative bacteria | 277001 |
Academy of Finland |
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Skok, Žiga, farmacevt | 39202 |
Barančokova, Michaela | 39784 |
Benek, Ondřej | ![]() |
Durante Cruz, Cristina | ![]() |
Tammela, Päivi | ![]() |
Tomašič, Tihomir | 28334 |
Zidar, Nace | 28905 |
Peterlin-Mašič, Lucija | 19317 |
Zega, Anamarija | 18633 |
Kikelj, Danijel | 01463 |
Ilaš, Janez | 24400 |
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