Second-generation 4,5,6,7-tetrahydrobenzo[ d ]thiazoles as novel DNA gyrase inhibitors

DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Building from our first generation of 4,5,6,7-tetrahydrobenzo[ ]thiazole-based DNA gyrase inhibitors, we design...

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Bibliographic Details
Published in:Future medicinal chemistry 2020-02, Vol.12 (4), p.277-297
Main Authors: Lamut, Andraž, Skok, Žiga, Barančoková, Michaela, Gutierrez, Lucas J, Cruz, Cristina D, Tammela, Päivi, Draskovits, Gábor, Szili, Petra Éva, Nyerges, Ákos, Pál, Csaba, Molek, Peter, Bratkovič, Tomaž, Ilaš, Janez, Zidar, Nace, Zega, Anamarija, Enriz, Ricardo D, Kikelj, Danijel, Tomašič, Tihomir
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial activity
Antibiotics
Benzothiazoles - chemistry
Benzothiazoles - pharmacology
Binding sites
Deoxyribonucleic acid
DNA
DNA Gyrase - metabolism
DNA topoisomerase
DNA topoisomerase IV
Dose-Response Relationship, Drug
Drug development
E coli
Enzymes
Gram-positive bacteria
Gram-Positive Bacteria - drug effects
Gram-Positive Bacteria - enzymology
Gram-Positive Bacteria - growth & development
Humans
Kinases
Microbial Sensitivity Tests
Microorganisms
Models, Molecular
Molecular Structure
Multidrug resistant organisms
Strains (organisms)
Structure-Activity Relationship
Thiazoles
Topoisomerase II Inhibitors - chemistry
Topoisomerase II Inhibitors - pharmacology
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Summary:DNA gyrase and topoisomerase IV are essential bacterial enzymes, and in the fight against bacterial resistance, they are important targets for the development of novel antibacterial drugs. Building from our first generation of 4,5,6,7-tetrahydrobenzo[ ]thiazole-based DNA gyrase inhibitors, we designed and prepared an optimized series of analogs that show improved inhibition of DNA gyrase and topoisomerase IV from and , with IC values in the nanomolar range. Importantly, these inhibitors also show improved antibacterial activity against Gram-positive strains. The most promising inhibitor, , is active against , and wild-type and resistant strains, with minimum inhibitory concentrations between 4 and 8 μg/ml, which represents good starting point for development of novel antibacterials.
ISSN:1756-8919
1756-8927
DOI:10.4155/fmc-2019-0127