Discovery of 4,5,6,7-Tetrahydrobenzo[1,2‑d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site

• Published in: Journal of medicinal chemistry 2015-07, Vol.58 (14), p.5501-5521
• Main Authors: Tomašič, Tihomir, Katsamakas, Sotirios, Hodnik, Žiga, Ilaš, Janez, Brvar, Matjaž, Solmajer, Tom, Montalvão, Sofia, Tammela, Päivi, Banjanac, Mihailo, Ergović, Gabrijela, Anderluh, Marko, Mašič, Lucija Peterlin, Kikelj, Danijel
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Binding Sites; DNA Gyrase - chemistry; DNA Gyrase - metabolism; DNA Topoisomerase IV - antagonists & inhibitors; Drug Design; Escherichia coli - drug effects; Escherichia coli - enzymology; Inhibitory Concentration 50; Models, Molecular; Protein Conformation; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - pharmacology; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00489

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 coli 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. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli 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 ΔtolC E. coli 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.