Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identifi...

Basic Information

ID: ALA4837261

Journal: J Med Chem

Title: 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.

Authors: Lu Y, Vibhute S, Li L, Okumu A, Ratigan SC, Nolan S, Papa JL, Mann CA, English A, Chen A, Seffernick JT, Koci B, Duncan LR, Roth B, Cummings JE, Slayden RA, Lindert S, McElroy CA, Wozniak DJ, Yalowich J, Mitton-Fry MJ.

Abstract: 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 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. This molecule demonstrates potent antibacterial activity against diverse Gram-positive 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.

CiteXplore: 34614347

DOI: 10.1021/acs.jmedchem.1c01250

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