The increasing global incidence of infections caused by free-living amoebae (FLA) and the lack of effective, safe, and approved treatments highlight the urgent need for novel amoebicidal compounds with pharmacological potential. Despite a growing body of literature on the anti-FLA properties of various compounds, comprehensive reviews summarizing this progress remain scarce. This study aimed to identify the most promising compounds tested in vitro and/or in vivo for anti-FLA activity. A systematic review was conducted, analyzing 108 studies published between 1986 and 2024, selected from an initial pool of 23,653 database results. A total of 537 compounds were evaluated for their in vitro anti-FLA activity. Compounds exhibiting ≥50% reduction in amoeba viability relative to untreated controls were classified as promising if they showed low toxicity in mammalian cell models, particularly when active at concentrations ≤ 10 µM, consistent with predicted favorable pharmacokinetic and pharmacodynamic profiles. The most promising compounds for drug and disinfectant development include ten trophocidal agents against B. mandrillaris, thirty-two trophocidal and four cysticidal agents against N. fowleri, and sixty-two trophocidal and nineteen cysticidal agents against Acanthamoeba spp. Compounds active at low concentrations (≤10 µM or <0.014 mg/mL) prioritized for in vivo drug development studies include: against Balamuthia mandrillaris, trophocidal 515, 531, 533; against Naegleria fowleri, trophocidal 421, 416, 518, 46, 254, 522, 111–120 and cysticidal 16; and against Acanthamoeba spp., trophocidal 498, 499, 500, 535, 107, 347, 348, and 340. Future studies should evaluate their efficacy, safety, pharmacokinetics, and pharmacodynamics toward developing effective drugs, antiseptics, and disinfectants.

Devastating or nearly invariably fatal infections caused by free-living amoebae (FLA), including Acanthamoeba keratitis (AK), granulomatous amoebic encephalitis (GAE), and primary amoebic meningoencephalitis (PAM), remain a significant public health concern, driven by increasing case numbers, geographic expansion, and the lack of approved, effective, and safe treatments. Despite decades of research, no new drugs have been successfully approved, highlighting the severe limitations of de novo drug development for these infections, particularly for GAE and PAM, largely due to the challenges of conducting clinical trials for these rare and rapidly lethal diseases. In this context, drug repurposing represents a cost-effective and promising strategy to accelerate therapeutic advances and overcome key bottlenecks of conventional drug development. Accordingly, we conducted a systematic review of in vitro studies and animal models of AK, GAE, and PAM reported in indexed databases to identify promising drug repurposing candidates against FLA infections. After screening 23,624 records, 112 studies were included in the analysis. Overall, 2726 drugs and drug combinations, spanning 865 pharmacological classes and approved for 565 therapeutic indications, were assessed for their repurposing potential. Among these, 166 compounds showed substantial trophocidal activity (≥IC₅₀) at potentially translatable concentrations (≤10 µM), including six with additional cysticidal activity. In vitro, four compounds were active against Balamuthia mandrillaris, 44 against Acanthamoeba spp. (three cysticidal), and 115 against Naegleria spp. (three cysticidal). In in vivo studies, sulfadiazine and rifampicin were effective as preventive or early monotherapies for GAE. For AK, the combination of polyhexamethylene biguanide, neomycin, and atropine, as well as voriconazole and nitazoxanide monotherapies, showed the greatest promise. In PAM, azithromycin alone or in combination with amphotericin B emerged as the most promising therapeutic options. Further studies are required to advance the clinical translatability of these findings. To the best of our knowledge, this work provides the first comprehensive and integrated synthesis of repurposable drug candidates against FLA infections.

Onychomycosis is a disease caused by fungi that affects the nails whose incidence is becoming increasingly frequent. The present study aimed the evaluation of the antifungal activity of essential oils from clove (Syzygium aromaticum), Chinese cinnamon (Cinnamomum cassia), rosemary (Rosmarinus officinalis) and basil (Ocimum basilicum), against the most prevalent dermatophytes implicated in onychomycosis: Trichophyton rubrum and Trichophyton mentagrophytes. The chemical composition of the oils was determined by GC-MS. The volatile oil of clove and Chinese cinnamon and basil presented, respectively, the phenylpropanoids eugenol (80.2%), E-cinnamaldehyde (99.4%) and methyl chavicol (68.81%) as the main components. The volatile oil of rosemary exhibited 1,8-cineole and camphor as the major compounds, representing 47% and 15% of the total content, respectively. The results obtained in broth microdilution tests indicate that basil oil presented the best antifungal potential against the tested strains of Trichophyton rubrum and Trichophyton mentagrophytes at concentrations that ranged from 8 mg/mL to 2 mg/mL. These findings point to the potential prospecting of Ocimum basilicum essential oil as a promising source of natural antimycotics to be subjected for further investigations.

The global rise in dermatophytosis prevalence, recurrence, and resistance underscores the urgent need for novel antifungal agents and alternative treatment strategies. This study provides the first report of the antidermatophytic activity of hyemaline, a natural alkaloid isolated from Zanthoxylum fagara, against clinically relevant dermatophytes, including Microsporum canis [minimum inhibitory concentration (MIC): 16-128 µg/mL], Trichophyton mentagrophytes (MIC: 2-128 µg/mL), and Trichophyton rubrum (MIC: 16-64 µg/mL). Mechanistic insights from molecular docking suggest hyemaline acts by inhibiting lanosterol 14-alpha demethylase (CYP51). Toxicity assessments conducted in silico and in vivo using a Drosophila melanogaster survival assay confirmed the compound's favorable safety profile. Additionally, in a D. melanogaster infection model, hyemaline treatment increased the survival of infected flies and achieved efficacy comparable to that of commercial antifungals. These findings establish hyemaline as a promising and safe antidermatophytic agent with a well-defined molecular target, warranting further development.