Efficacy of a Novel Tricyclic Topoisomerase Inhibitor in a Murine Model of Neisseria gonorrhoeae Infection

Abstract

There is an urgent need for new antibiotics to treat multidrug-resistant Neisseria gonorrhoeae. In this report, the microbiology, in vivo pharmacokinetics, and efficacy of REDX05931, a representative novel tricyclic topoisomerase inhibitor, were evaluated. REDX05931 demonstrated high oral bioavailability in mice and reduced N. gonorrhoeae infection after a single dose in a mouse model of gonorrhea. These data support the potential of this series of small molecules as a new treatment for drug-resistant gonorrheal infections.

In Vitro and In Vivo Activities of TP0480066, a Novel Topoisomerase Inhibitor, against Neisseria gonorrhoeae

“…Mouse model of N. gonorrhoeae. A mouse genital tract infection model (38)(39)(40) was used to evaluate the in vivo effect of TP0480066 (n = 5 to 8). Female BALB/c mice were purchased from Japan SLC, Inc. (Shizuoka, Japan) at 6 weeks of age and allowed to acclimate to the animal facility for 3 days.…”

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1

“…34 This compound was then progressed to a murine model of N. gonorrhoeae infection with encouraging results. 35 However, due to inhibition of several CYP enzymes (Table 3) and a potential interaction with the hERG ion channel, REDX05931 was not developed further. A range of other methylene amine derivatives were prepared.…”

“…Synthesis of REDX05237 began with the formation of the isatin (34) from 4-fluoro-2-methyl-aniline (33) and chloral hydrate in HCl, followed by the addition of hydroxylamine hydrochloride. 56 As we were unable to selectively mono-brominate at the 6 position of the isatin, this was bisbrominated with NBS to give the (35) which was then selectively mono-debrominated with the use of copper and propionic acid. 57 The regioselectivity of the monodebrominated product (36) was confirmed by NMR.…”

“…It also demonstrated an excellent microbiological profile against a range of resistant Neisseria gonorrhoeae strains with MICs ranging from 0.06 to 1 μg mL −1 . 34,35 It is noteworthy to add, however, that there was no measured activity against Escherichia coli (E. coli), possibly due to the relatively high lipophilicity (measured log D = 2.96) observed for REDX04139, which is known to disfavor permeability into Gram-negative bacteria. 36,37 REDX04139 had low thermodynamic solubility at physiological pH (3 μM).…”

“…4), focusing on modifications of the core (X and R 1 ), R 4 substitution (aromatic and saturated heterocycles), as well as simple substitution at the oxazole 2-position (R 3 ). Since our initial publications, 34,35 two papers on an imidazopyrazinones (IPYs) series have been published which have a similar scientific rationale to our novel tricyclic topoisomerase inhibitor (NTTI) series. Although similar, the IPY series did not demonstrate superior potency to the NTTI series and displayed genotoxic liabilities.…”