Products Cited in Publications Worldwide 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

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

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.

DOI: PMID:

Abstract

Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclin./clin. development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound 79 (I). This mol. demonstrates potent antibacterial activity against diverse Gram-pos. pathogens, inhibition of both DNA gyrase and topoisomerase IV, a low frequency of resistance, a favorable in vitro cardiovascular safety profile, and in vivo efficacy in a murine model of methicillin-resistant Staphylococcus aureus infection.

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