Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5‑Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with In Vivo Efficacy against MRSA

Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimiz...

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Veröffentlicht in:	Journal of medicinal chemistry 2021-10, Vol.64 (20), p.15214-15249
Hauptverfasser:	Lu, Yanran, Vibhute, Sandip, Li, Linsen, Okumu, Antony, Ratigan, Steven C, Nolan, Sheri, Papa, Jonathan L, Mann, Chelsea A, English, Anthony, Chen, Anna, Seffernick, Justin T, Koci, Bryan, Duncan, Leonard R, Roth, Brieanna, Cummings, Jason E, Slayden, Richard A, Lindert, Steffen, McElroy, Craig A, Wozniak, Daniel J, Yalowich, Jack, Mitton-Fry, Mark J
Format:	Artikel
Sprache:	eng
Schlagworte:	Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Dioxanes - chemical synthesis Dioxanes - chemistry Dioxanes - pharmacology DNA Gyrase - metabolism DNA Topoisomerase IV - antagonists & inhibitors DNA Topoisomerase IV - metabolism Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Ether-A-Go-Go Potassium Channels - antagonists & inhibitors Ether-A-Go-Go Potassium Channels - metabolism Humans Methicillin-Resistant Staphylococcus aureus - drug effects Microbial Sensitivity Tests Molecular Structure Structure-Activity Relationship
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