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.
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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
(14), 5501-5521. https://doi.org/10.1021/acs.jmedchem.5b00489