Quinolones as anti-Toxoplasma agents: a comprehensive scoping review of in vitro and in vivo efficacy

Toxoplasmosis is a globally prevalent parasitic disease with significant therapeutic limitations, especially in vulnerable populations. This scoping review assesses the efficacy of quinolones against Toxoplasma gondii in vitro and in vivo. PubMed, ScienceDirect, Web of Science, Embase, Scopus, ProQuest, and Google Scholar were searched from inception to August 2024. Original English-language studies evaluating quinolone effects on T. gondii were included. Screening and data extraction followed PRISMA 2020 guidelines. Of 5,252 initial records, 29 studies were shortlisted for final qualitative synthesis. In vitro analysis revealed a stark dichotomy: while clinical fluoroquinolones such as ciprofloxacin (IC50 = 3.44–20 µM) possessed weak-to-moderate activity, experimental scaffolds, particularly Hydroxyquinolone derivatives (e.g., Compound A, IC50 = 0.0004 μM) and endochin-like quinolones (ELQs) (e.g., ELQ-316, IC50 = 0.000007 μM) achieved sub-nanomolar potency by inhibiting the mitochondrial electron transport chain. Structural optimization was essential; for example, adamantane-conjugated ciprofloxacin (Adam-Cipro) was 31-fold more potent than the parent drug (IC50 = 0.64 µM vs. 20 µM). Combination regimens (e.g., gatifloxacin-pyrimethamine) maximized efficacy while also lowering resistance risks. Novel compounds such as ELQ-316 (0.08 mg/kg) decreased brain cyst burden by up to 88% in chronic models and provided complete protection in acute models. Translational challenges were identified, including the failure of decoquinate (DCQ) to suppress vertical transmission in pregnancy models and the emergence of resistance to ELQ-316. Key research gaps persist: the activity of quinolones against latent bradyzoites, efficacy in immunocompromised hosts, and safety in children and pregnant women remain unexplored. This review demonstrates that while conventional clinical quinolones are suboptimal against T. gondii, structure-optimized quinolones targeting the parasite mitochondria can yield outstanding potency. Efficacy is determined by precise structure activity relationships (particularly at the C-7 position) and advanced drug delivery systems. Despite ongoing translational challenges such as bioavailability optimization, tissue penetration barriers, and resistance management new quinolone compounds and combination regimens hold great promise as anti-Toxoplasma drugs.