Novel N-Linked Aminopiperidine-Based Gyrase Inhibitors with Improved hERG and in Vivo Efficacy against Mycobacterium tuberculosis

Abstract

DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.

Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs

“…During the preparation of the manuscript, a closely related class of N-linked aminopiperidinyl-based gyrase inhibitors was described by AstraZeneca (16). M. tuberculosis DNA gyrase supercoiling and the cleavage complex assays confirmed their mode of action.…”

“…This exercise resulted in the identification of novel M. tuberculosis DNA gyrase inhibitors (MGIs), a new family of promising compounds with potential for the treatment of TB disease already reported in the literature as antimycobacterial and antibacterial agents (12,13,14,15). Recently, AstraZeneca has reported anti-TB activity for NBTIs (16).…”

Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding

“…This data suggests that R 1 substituents at the C-7 position of the LHS ring is amenable for chemical diversity Fluoro substituted aminopiperidine based NBTIs have shown good oral bioavailability and hERG selectivity as compared to their nonfluoro counterparts. 8,9 In order to identify compounds with good oral pharmacokinetic properties, we introduced a fluoro substitution in the linker portion of compounds 10 and 11 to result in compounds 18 and 19, respectively. This The scatter plot presented in Figure 3 for hERG IC 50 suggested that calculated lipophilicity (AZ logD) of <1.5 is ideal for achieving good hERG selectivity for compounds with bulky substitutions at R 1 position of LHS ring (green encircled in Figure 3).…”

“…[8][9][10]16 The synthesis of compounds with bulky substitutions (2−9) are illustrated in Scheme 1. Nucleophilic displacement of halo substituted naphthyridones (I) with corresponding carbinol (II) using cesium carbonate under thermal heating condition resulted in title compounds 2−19.…”

“…Thus, the large polar bulky substitution at the C-7 position does not change the potency and hERG selectivity among the compounds reported in Table 2 A homology model based on the binding mode of aminopiperidine based NBTIs to Mtb GyrA has been reported. 8,16 In order to understand the effect of bulky polar substitutions on NBTIs binding to Mtb GyrA subunit, we docked compounds 2 and 3. The possible binding modes of compounds 2 and 3 in the Mtb GyrA homology model are depicted in Figure 2.…”