2. Academic Validation
  3. Amoebicidal thymol analogues against brain-eating amoeba, Naegleria fowleri

Amoebicidal thymol analogues against brain-eating amoeba, Naegleria fowleri

  • Bioorg Chem. 2025 Mar 6:159:108346. doi: 10.1016/j.bioorg.2025.108346.
Meriam Ben Youssef 1,  Amani Omrani 1,  Ines Sifaoui 2,  Eduardo Hernández-Álvarez 3,  Javier Chao-Pellicer 2,  Isabel L Bazzocchi 3,  Hichem Sebai 4,  José E Piñero 2,  Ignacio A Jimenez 5,  Jacob Lorenzo-Morales 2
Affiliations

Affiliations

  • 1 Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296 La Laguna, Tenerife, Spain; Laboratory of Functional Physiology and Valorization of Bio-Ressources, Higher Institute of Biotechnology of Beja, University of Jendouba, Beja 382-9000, Tunisia; Instituto Universitario de Bio-Orgánica Antonio González, and Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.
  • 2 Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, 38296 La Laguna, Tenerife, Spain; Departamento de Obstetricia y Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad de La Laguna, C/ Sta. María Soledad s/n, 38200 La Laguna, Tenerife, Spain; Consorcio Centro de Investigación Biomédica en Red, Área de Enfermedades Infecciosas (CIBERINFECT), Instituto de Salud Carlos III, Av. Monforte de Lemos 3-5, Pabellón 11, 28029 Madrid, Spain.
  • 3 Instituto Universitario de Bio-Orgánica Antonio González, and Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.
  • 4 Laboratory of Functional Physiology and Valorization of Bio-Ressources, Higher Institute of Biotechnology of Beja, University of Jendouba, Beja 382-9000, Tunisia.
  • 5 Instituto Universitario de Bio-Orgánica Antonio González, and Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain. Electronic address: ignadiaz@ull.edu.es.
PMID: 40107039 DOI: 10.1016/j.bioorg.2025.108346
Abstract

Naegleria fowleri, known as the brain-eating amoeba, is the pathogen Parasite that causes primary amoebic meningoencephalitis. None of the currently available therapies are fully effective, mainly due to the inefficacy of pharmacotherapy. In this regard, Natural Products and related compounds represent a promising strategy for amoebicidal drug discovery. Herein, a series of eight monoterpene phenol derivatives of thymol bearing ester, carbonate, or carbamate moieties were prepared, and screened as potential amoebicidal agents on N. fowleri. The cytotoxicity of these compounds on murine macrophages cell line J774 was also evaluated to assess their selectivity. Compounds 3, 4, 7 and 8 showed significant activity against the N. fowleri trophozoite. Moreover, 4-nitrophenyl thymyl carbonate 8 displayed the highest potency, showing IC50 values of 22.87 and 25.16 μM against N. fowleri trophozoite and cyst stages, respectively, coupled with low cytotoxicity on a mammal cell line. Furthermore, mechanism of action studies revealed that derivative 8 triggered programmed cell death via cytosolic calcium accumulation, mitochondrial alteration, membrane damage, chromatin condensation, and ROS accumulation. In addition, the in-silico ADME analysis indicated that derivative 8 exhibits exceptional drug-likeness meeting all the pharmacokinetic criteria. These results highlight derivative 8 as a promising amoebicidal agent to develop new drugs for the treatment of Naegleria infections.

Keywords

Amoebicidal activity; Drug-likeness; Mechanism of action; Naegleria fowleri; Thymol derivatives.

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