Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with In Vivo Efficacy against MRSA

Yanran Lu, Sandip Vibhute, Linsen Li, Antony Okumu, Steven C. Ratigan, Sheri Nolan, Jonathan L. Papa, Chelsea A. Mann, Anthony English, Anna Chen, Justin T. Seffernick, Bryan Koci, Leonard R. Duncan, Brieanna Roth, Jason E. Cummings, Richard A. Slayden, Steffen Lindert, Craig A. McElroy, Daniel J. Wozniak, Jack Yalowich, and Mark J. Mitton-Fry*  – Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States

topisomeraseJMC cmpds

J. Med. Chem. 2021, 64, 20, 15214–15249

We like a med chem paper with novel anti-bacterial compounds so our eye was drawn to these Topoisomerase Inhibitors. The paper describes the synthesis of compounds with a ‘dioxane linker’ between two aromatic groups. Compounds were made using late-stage intermediates and available heterocycles to drive SAR understanding. The paper is rich in test data for multiple strains of bacteria (including Gram -ve) and many examples have good activity.  We point out Table2 as general interest to medicinal chemists; there a several excellent isosteres for aromatic groups, in particular 3,4-dichlorobenzene (these are the kind of matched pairs we are interested in, and these data will be assimilated into our collective). Some effort by the researches was put in to improving the metabolism of the compounds, sadly without a breakthrough result, but the approach is worth noting. Finally, efforts to reduce hERG binding of the series led to compound 79 with improved margin.  It seems that many modern anti-bacterial research compounds seem to all suffer from some degree of hERG inhibition. The PK profile of 79 was acceptable to plan an in-vivo efficacy study (F% 49%) and it showed >50% survival rate in infected mice after 7 days.