Discovery of Novel DNA Gyrase Inhibiting Spiropyrimidinetriones: Benzisoxazole Fusion with N-Linked Oxazolidinone Substituents Leading to a Clinical Candidate (ETX0914)

Abstract

A novel class of bacterial type-II topoisomerase inhibitor displaying a spiropyrimidinetrione architecture fused to a benzisoxazole scaffold shows potent activity against Gram-positive and fastidious Gram-negative bacteria. Here, we describe a series of N-linked oxazolidinone substituents on the benzisoxazole that improve upon the antibacterial activity of initially described compounds of the class, show favorable PK properties, and demonstrate efficacy in an in vivo Staphylococcus aureus infection model. Inhibition of the topoisomerases DNA gyrase and topoisomerase IV from both Gram-positive and a Gram-negative organisms was demonstrated. Compounds showed a clean in vitro toxicity profile, including no genotoxicity and no bone marrow toxicity at the highest evaluated concentrations or other issues that have been problematic for some fluoroquinolones. Compound 1u was identified for advancement into human clinical trials for treatment of uncomplicated gonorrhea based on a variety of beneficial attributes including the potent activity and the favorable safety profile.

The utilization of spirocyclic scaffolds in novel drug discovery

“…The spirocyclic feature in this series was originally introduced based on modeling and subsequently optimized for improved physical properties and metabolic stability. Pyrimidinetrione 6 is a DNA gyrase inhibitor which has entered clinical trials for the treatment of gonorrhea [15]. The spirocyclic feature in 6 was present in a member of a compound library screened for antibacterial activity.…”

“…The oxindole ring mimics the Trp23 side chain in p53 with the NH group of the oxindole ring forming hydrogen bonds to Leu54 of MDM2 (protein databank (PDB) codes 1YCR and 3LBL). Spirocyclic glycoside tofogliflozin (15) is an inhibitor of human sodium glucose cotransporter 2 (hSGLT2) and was approved in 2014 in Japan for the treatment of Type 2 diabetes [27]. A pharmacophore query based on known hSGLT2 inhibitors was developed and searched against a database of threedimensional structures.…”

Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers

“…Zoliflodacin antibacterial activity has been extensively evaluated in preclinical studies (5,7,9,10). In vitro studies have shown that resistant Gram-positive and Gramnegative pathogens, including fluoroquinolone-and vancomycin-resistant staphylococci and ciprofloxacin-, ceftriaxone-, and penicillin-resistant N. gonorrhoeae, remain sensitive to zoliflodacin (6,8,11,12).…”

Endless resistance. Endless antibiotics?

“…Notwithstanding this similarity and the shared target, the mechanistic difference between the two is distinct. 74,75 ETX-0914 is a clinical candidate targeting Neisseria gonorrhoeae . It is discussed in this review as an outstanding example of the possible value that synthetic chemical libraries may have for the discovery of new antibacterials.…”