Discovery of 4,5,6,7-tetrahydrobenzo[1,2-d]thiazoles as novel DNA gyrase inhibitors targeting the ATP-binding site

Tihomir Tomašič, Sotirios Katsamakas, Žiga Hodnik, Janez Ilaš, Matjaž Brvar, Tom Solmajer, Sofia Montalvao, Päivi Tammela, Mihailo Banjanac, Gabrijela Ergović, Marko Anderluh, Lucija Peterlin Mašič, Danijel Kikelj

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Sammanfattning

Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coil DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo [1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coil DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coil topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and Delta tolC E. coil strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
Originalspråkengelska
TidskriftJournal of Medicinal Chemistry
Volym58
Utgåva14
Sidor (från-till)5501-5521
Antal sidor21
ISSN0022-2623
DOI
StatusPublicerad - 23 jul 2015
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 317 Farmaci

Citera det här

Tomašič, T., Katsamakas, S., Hodnik, Ž., Ilaš, J., Brvar, M., Solmajer, T., ... Kikelj, D. (2015). Discovery of 4,5,6,7-tetrahydrobenzo[1,2-d]thiazoles as novel DNA gyrase inhibitors targeting the ATP-binding site. Journal of Medicinal Chemistry, 58(14), 5501-5521. https://doi.org/10.1021/acs.jmedchem.5b00489