Second-Generation Antibacterial Benzimidazole Ureas: Discovery of a Preclinical Candidate with Reduced Metabolic Liability

Abstract

Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation.

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

“…binding modes reported for closely related compounds in complex with the highly homologous gyrase B from Staphylococcus aureus (13). The model suggests that the S208A mutation negatively affects the binding of VXc-486 to M. tuberculosis gyrase B by altering the hydrogen bonding network and destabilizing the catalytic water present in the active site (see Fig.…”

“…Further optimization of the metabolic profile led to the identification of VXc-486 (13), and its solubility was later improved by using a phosphate prodrug approach (O'Dowd DS, Chandupatla HK, Bennani Y, Engtrakul J, Ye Z, Yeola S, Liao S, Ewing N, Jones P, Tsao H, Kolaczkowski E, Donahue S, Seliniotakis R, Bao N, Tsai A, Shawgo R, Dixit V, Jones S, McNeil CF, Song B, Macikenas D, Grillot A-L, Charifson P, unpublished data). The purpose of this study was to explore the utility of VXc-486 and its phosphate prodrug (pVXc-486) against…”

Synthesis and Evaluation of N‐Phenylpyrrolamides as DNA Gyrase B Inhibitors

“…[6] The second possible mechanism of action of drugs targeting DNA gyrase and topoisomerase IV involves inhibition of ATPb inding at the GyrB/ParEs ubunit. Novobiocin,anatural aminocoumarin antibiotic that was withdrawn from the clinic because of toxicity and al ack of efficacy, [7] is ac lassic example of an ATP-com-petitiveG yrB inhibitor.I nr ecent decades, several new scaffolds have been identified as GyrB and/orP arE inhibitors, such as pyridylureas, [8] pyrimidinoindoles, [9] pyrrolopyrimidines, [10] benzimidazole ureas, [11] pyrrolamides, [12] and pyrazolopyridones [13] (Figure 1). Although some of these new inhibitors have advancedt op hase It rials, none have so far reached clinical practice.…”

The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases

“…Gyrase B was singled out because several Gyrase B-ligand complexes are available with affinities in the nanomolar range. 48–50 Moreover, a Gyrase B ligand has been reported to bind to the ATP-domain of HKs. 45,47 We decided to focus on the complex PDB: 3TTZ because the ligand 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl]-1,3-thiazole-5-carboxylic acid (pyrrolamide, Figure 3 D) has an 50% inhibitory concentration (IC 50 ) value of 4 nM.…”