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Amoebicidal thymol analogues against brain-eating amoeba, Naegleria fowleri

Meriam Ben Youssef1, Amani Omrani1, Ines Sifaoui2

  • 1Instituto 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.

Bioorganic Chemistry
|March 19, 2025
PubMed

Insights

New thymol derivatives show promise against the brain-eating amoeba, Naegleria fowleri. Compound 8 effectively killed amoeba stages with low mammal cell toxicity, suggesting potential for new treatments.

Area of Science:

  • Medicinal Chemistry
  • Parasitology
  • Drug Discovery

Background:

  • Naegleria fowleri causes fatal primary amoebic meningoencephalitis.
  • Current therapies for Naegleria infections are largely ineffective.
  • Natural products offer a promising avenue for novel amoebicidal drug development.

Purpose of the Study:

  • To synthesize and screen thymol derivatives as potential amoebicidal agents against Naegleria fowleri.
  • To evaluate the cytotoxicity and selectivity of these derivatives on mammalian cells.
  • To investigate the mechanism of action and pharmacokinetic properties of the most potent compound.

Main Methods:

  • Synthesis of eight monoterpene phenol derivatives of thymol.
  • Screening of compounds against Naegleria fowleri trophozoites and cysts.
  • Cytotoxicity assessment on murine macrophage cell line J774.
  • Mechanism of action studies including calcium, mitochondrial, membrane, chromatin, and ROS analysis.
  • In-silico ADME analysis for drug-likeness.

Main Results:

  • Compounds 3, 4, 7, and 8 demonstrated significant activity against N. fowleri.
  • 4-nitrophenyl thymyl carbonate 8 exhibited the highest potency (IC50: 22.87 μM for trophozoites, 25.16 μM for cysts) with low cytotoxicity.
  • Derivative 8 induced programmed cell death via multiple cellular pathways.
  • In-silico analysis confirmed excellent drug-likeness and pharmacokinetic properties for derivative 8.

Conclusions:

  • Thymol derivative 8 is a highly promising candidate for developing new drugs against Naegleria infections.
  • The compound's potent amoebicidal activity, low cytotoxicity, and favorable pharmacokinetic profile warrant further investigation.
  • This study highlights the potential of natural product derivatives in addressing unmet medical needs for parasitic infections.
Keywords:
Amoebicidal activityDrug-likenessMechanism of actionNaegleria fowleriThymol derivatives

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