Zoliflodacin

Zoliflodacin

• CAS 1620458-09-4
• AZD-0914
• AZD0914
• FWL2263R77
• ETX0914

MF C₂₂H₂₂FN₅O₇ MW 487.4 g/mol

FDA 2025, APPROVALS 2025, 12/12/2025, Nuzolvence

(4′R,6′S,7′S)-17′-fluoro-4′,6′-dimethyl-13′-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]spiro[1,3-diazinane-5,8′-5,15-dioxa-2,14-diazatetracyclo[8.7.0.0^2,7.0^12,16]heptadeca-1(17),10,12(16),13-tetraene]-2,4,6-trione

Spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione, 11-fluoro-1,2,4,4a-tetrahydro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-3-oxazolidinyl]-, (2R,4S,4aS)-

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione

To treat uncomplicated urogenital gonorrhea due to Neisseria gonorrhoeae

Zoliflodacin, sold under the brand name Nuzolvence, is an antibiotic used for the treatment of antibiotic-resistant Neisseria gonorrhoeae (gonorrhea).^[2] Zoliflodacin is being developed as part of a public-private partnership between Innoviva Specialty Therapeutics and the Global Antibiotic Research & Development Partnership (GARDP).^[3] Zoliflodacin is taken by mouth.^[2]

The most common side effects include low white blood cell counts, headache, dizziness, nausea, and diarrhea.^[2]

Zoliflodacin was approved for medical use in the United States in December 2025.^[2]

SYN

• Facile Synthesis of Spirocyclic Tetrahydroquinolines via C(sp3)–H Functionalization in a Cascade Redox ProcessDOI: 10.1055/s-0040-1720890Publication Date: 2022Publication Name: Synthesis
• Synthesis of ZoliflodacinDOI: 10.1055/s-0040-1707088Publication Date: 2020Publication Name: Synfacts

SYN

SYN

US8889671, 5

SYN

WO-2022204231-A2

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US106042502&_cid=P11-MJMADN-82597-1

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione

Example 5 was prepared from Intermediate 21. The title compound was isolated by reverse phase HPLC (10 mM ammonium acetate in water, CH 3CN) as the first eluting of two components. 1H NMR (400 MHz, DMSO-d 6) δ: 0.9 (d, 3H), 1.15 (d, 3H), 1.4 (d, 3H), 2.9 (d, 1H), 3.1 (t, 1H), 3.5-3.6 (m, 2H), 3.8 (m, 1H), 3.9 (d, 1H), 4.0 (d, 1H), 4.2 (q, 1H), 4.6-4.7 (m, 2H), 7.6 (s, 1H), 11.5 (s, 1H), 11.8 (s, 1H). MS (ES) MH +: 488.4 for C 22H 22FN 5O 7, [α] D 20=−92 (c=1; MeOH).

Also isolated from the synthesis of Example 5 as the second eluting component from HPLC purification was (2S,4R,4aR)-11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione

1H NMR (400 MHz, DMSO-d 6) δ: 0.9 (d, 3H), 1.15 (d, 3H), 1.4 (d, 3H), 2.9 (d, 1H), 3.1 (t, 1H), 3.6-3.7 (m, 2H), 3.8-4.0 (m, 1H), 3.9 (d, 1H), 4.1 (d, 1H), 4.2 (q, 1H), 4.6-4.7 (m, 2H), 7.6 (s, 1H), 11.5 (s, 1H), 11.8 (s, 1H). MS (ES) MH +: 488.4 for C 22H 22FN 5O 7, [α] D 20=+224 (c=1; MeOH).

Alternative Synthesis of Example 5

A solution of Intermediate 22 (1.14 g, 2.71 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (0.346 g, 2.71 mmol) in acetic acid (8 mL) and of water (2 mL) was heated at 110° C. for 2 hours. The solvent was removed and the reaction mixture was purified using Super Critical Fluid Chromatography (Chiralpak IC column with 30% methanol and 70% CO 2 mobile phase). The first eluting compound was further purified by dissolving in acetonitrile (30 mL) and diluting with water (60 mL) to give the title compound as a solid. (0.910 g, 69.0% yield). 1H NMR (300 MHz, DMSO-d 6) δ: δ 0.9 (d, 3H), 1.15 (d, 3H), 1.4 (d, 3H), 2.9 (d, 1H), 3.1 (t, 1H), 3.6-3.7 (m, 2H), 3.8 (m, 1H), 3.9 (d, 1H), 4.1 (d, 1H), 4.2 (q, 1H), 4.6-4.75 (m, 2H), 7.6 (s, 1H), 11.4 (s, 1H), 11.8 (s, 1H). MS (ES) MH +: 488 for C 22H 22FN 6O 7.

Also isolated from the synthesis of Alternative Synthesis of Example 5 as the second component eluting from the HPLC purification was (2R,4R,4aR)-11-fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione:

 ¹H NMR (300 MHz, DMSO-d ₆) δ: 1.0 (d, 3H), 1.3 (d, 3H), 1.4 (d, 3H), 3.1 (d, 1H), 3.5-4.3 (m, 7H), 4.5-4.8 (m, 2H), 7.6 (s, 1H), 11.5 (br. s., 1H), 11.7 (br. s., 1H). MS (ES) MH ⁺: 488 for C ₂₂H ₂₂FN ₅O ₇.

SYN

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/mic90

2.3.2 Chemical synthesis

The synthesis of zoliflodacin described below was reported in 2015 [47]. The first step, starting from 2,3,4-trifluorobenzaldehyde, consists of the protection of the aldehyde function to an acetal group. After deprotonation using n-BuLi, formylation is performed with DMF to introduce an aldehyde group, which is then converted to oxime using hydroxylamine. Chlorination with N-chlorosuccinimide (NCS), followed by reaction with L-alaninol and intramolecular S_NAr allows the formation of the benzisoxazole ring. The oxazolidinone moiety is obtained using 1,1′-carbonyldiimidazole (CDI). The deprotection of the aldehyde is then performed in acidic conditions followed by another S_NAr at the ortho position of the aldehyde using (2R,6S)-2,6-dimethylmorpholine. Finally, a Knoevenagel condensation between the aldehyde and hexahydropyrimidine-2,4,6-trione is performed, followed by an intramolecular rearrangement consisting in an [1-5] hydride shift and then intramolecular cyclization leading to zoliflodacin (Fig. 5).

PAT

• High throughput screening assay to identify DNA topoisomerase inhibitorsPublication Number: US-12234504-B1Priority Date: 2023-10-16Grant Date: 2025-02-25
• Treatment of pathogenic neisseria sp. infection with triazole antifungal agentsPublication Number: US-2025281464-A1Priority Date: 2022-04-29
• Methods and materials for treatment of neisseria gonorrhoeae infectionPublication Number: WO-2022204231-A2Priority Date: 2021-03-26
• Methods and materials for treatment of neisseria gonorrhoeae infectionPublication Number: EP-4313040-A2Priority Date: 2021-03-26
• Methods and materials for treatment of neisseria gonorrhoeae infectionPublication Number: EP-4313040-A2Priority Date: 2021-03-26

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Medical uses

Zoliflodacin is indicated for the treatment of uncomplicated urogenital gonorrhea in people who weigh at least 77 pounds (35 kg).^[2]

Susceptible bacteria

Zoliflodacin has shown in vitro activity against the following species of bacteria:^[4] Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Chlamydia trachomatis

Adverse effects

Animal studies showed that zoliflodacin might cause birth defects, pregnancy loss, or male fertility problems.^[2]

Mechanism of action

It has a mechanism of action which involves inhibition of bacterial type II topoisomerases.^[4][5][6]

History

A high throughput screening campaign aimed at identifying compounds with whole cell antibacterial activity performed at Pharmacia & Upjohn identified compound PNU-286607, a progenitor of Zoliflodacin, as having the desired activity.^[7]

Subsequent research at AstraZeneca led to the discovery that the nitroaromatic in PNU-286607 could be replaced with a fused benzisoxazole ring,^[8] which allowed for an exploration of different groups at the 3-position of the heterocycle. This work was continued at Entasis Pharmaceuticals where extensive optimization resulted in the discovery of ETX0914.^[4]

Researchers tested zoliflodacin in a study with 930 participants who had uncomplicated urogenital gonorrhea.^[2] Two-thirds of participants received a single 3-gram dose of zoliflodacin dissolved in water.^[2] The other third received the standard treatment of ceftriaxone shot plus azithromycin pill.^[2] The study measured how well the medicines cleared the bacteria 4 to 8 days after treatment.^[2] The study showed 91% of participants who took zoliflodacin were cured and 96% of participants who received the standard treatment were cured.^[2]

Society and culture

Legal status

Zoliflodacin was approved for medical use in the United States in December 2025.^[3]

The US Food and Drug Administration (FDA) granted the application for zoliflodacin fast track, qualified infectious disease product, and priority review designations for the uncomplicated urogenital gonorrhea indication.^[2] The FDA approval for zoliflodacin was granted to Entasis Therapeutics.^[2]

Names

Zoliflodacin is the international nonproprietary name.^[9]

Zoliflodacin is sold under the brand name Nuzolvence.^[3]

References

1.  https://innovivaspecialtytherapeutics.com/wp-content/uploads/2025/12/NUZOLVENCE-zoliflodacin-Full-Prescribing-Information-December-2025.pdf ^{[bare URL PDF]}
2.  “FDA Approves Two Oral Therapies to Treat Gonorrhea”. U.S. Food and Drug Administration (FDA) (Press release). 12 December 2025. Retrieved 13 December 2025.  This article incorporates text from this source, which is in the public domain.
3.  Pierre G (12 December 2025). “Nuzolvence (Zoliflodacin) Receives U.S. FDA Approval”. Global Antibiotic Research & Development Partnership (GARDP). Retrieved 13 December 2025.
4.  Basarab GS, Kern GH, McNulty J, Mueller JP, Lawrence K, Vishwanathan K, et al. (July 2015). “Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases”. Scientific Reports. 5 (1) 11827. Bibcode:2015NatSR…511827B. doi:10.1038/srep11827. PMC 4501059. PMID 26168713.
5.  Bradford PA, Miller AA, O’Donnell J, Mueller JP (June 2020). “Zoliflodacin: An Oral Spiropyrimidinetrione Antibiotic for the Treatment of Neisseria gonorrheae, Including Multi-Drug-Resistant Isolates”. ACS Infectious Diseases. 6 (6): 1332–1345. doi:10.1021/acsinfecdis.0c00021. PMID 32329999.
6.  Pisano L, Giovannuzzi S, Supuran CT (June 2024). “Management of Neisseria gonorrhoeae infection: from drug resistance to drug repurposing”. Expert Opinion on Therapeutic Patents. 34 (6): 511–524. doi:10.1080/13543776.2024.2367005. PMID 38856987.
7.  Miller AA, Bundy GL, Mott JE, Skepner JE, Boyle TP, Harris DW, et al. (August 2008). “Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors”. Antimicrobial Agents and Chemotherapy. 52 (8): 2806–2812. doi:10.1128/AAC.00247-08. PMC 2493097. PMID 18519725.
8.  Basarab GS, Brassil P, Doig P, Galullo V, Haimes HB, Kern G, et al. (November 2014). “Novel DNA gyrase inhibiting spiropyrimidinetriones with a benzisoxazole scaffold: SAR and in vivo characterization”. Journal of Medicinal Chemistry. 57 (21): 9078–9095. doi:10.1021/jm501174m. PMID 25286019.
9.  World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 76”. WHO Drug Information. 30 (3). hdl:10665/331020.

Further reading

• Luckey A, Balasegaram M, Barbee LA, Batteiger TA, Broadhurst H, Cohen SE, et al. (2025). “Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial”. The Lancet. doi:10.1016/S0140-6736(25)01953-1.
• Taylor SN, Marrazzo J, Batteiger BE, Hook EW, Seña AC, Long J, et al. (November 2018). “Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea”. The New England Journal of Medicine. 379 (19): 1835–1845. doi:10.1056/NEJMoa1706988. hdl:1805/19865. PMID 30403954.

External links

• Clinical trial number NCT03959527 for “Zoliflodacin in Uncomplicated Gonorrhoea” at ClinicalTrials.gov

Clinical data
Trade names	Nuzolvence
Other names	AZD0914; ETX0914
AHFS/Drugs.com	Nuzolvence
License data	US DailyMed: Zoliflodacin
Routes of administration	By mouth
Drug class	Antibacterial
ATC code	None
Legal status
Legal status	US: ℞-only[1][2]
Pharmacokinetic data
Bioavailability	97.8%
Metabolism	Liver
Onset of action	Fasted: 1.5–2.3 hFed: 4 h
Elimination half-life	5.3–6.3 h
Excretion	Feces (79.6%)Urine (18.2%)
Identifiers
IUPAC name
PubChem CID	76685216
DrugBank	12817
UNII	FWL2263R77
KEGG	D11726
Chemical and physical data
Formula	C22H22FN5O7
Molar mass	487.444 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

//////////Zoliflodacin, FDA 2025, APPROVALS 2025, Nuzolvence, AZD-0914, AZD 0914, FWL2263R77, ETX 0914