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.

Autor:	Lu Y; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Vibhute S; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Li L; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Okumu A; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Ratigan SC; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Nolan S; Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio 43210, United States., Papa JL; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Mann CA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., English A; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Chen A; Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio 43210, United States., Seffernick JT; Department of Chemistry and Biochemistry, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, United States., Koci B; Eurofins Panlabs, St. Charles, Missouri 63304, United States., Duncan LR; JMI Laboratories, North Liberty, Iowa 52317, United States., Roth B; JMI Laboratories, North Liberty, Iowa 52317, United States., Cummings JE; Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, United States., Slayden RA; Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, United States., Lindert S; Department of Chemistry and Biochemistry, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, United States., McElroy CA; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Wozniak DJ; Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio 43210, United States.; Department of Microbiology, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, United States., Yalowich J; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States., Mitton-Fry MJ; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Oct 28; Vol. 64 (20), pp. 15214-15249. Date of Electronic Publication: 2021 Oct 06.
DOI:	10.1021/acs.jmedchem.1c01250
Abstrakt:	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.
Databáze:	MEDLINE
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