Naphthyridine Derivatives Induce Programmed Cell Death in Naegleria fowleri

Area of Science:

• Medicinal Chemistry
• Parasitology
• Molecular Biology

Background:

• Primary amoebic encephalitis (PAM) is a rapidly fatal brain infection caused by Naegleria fowleri.
• Naegleria fowleri is an opportunistic amoeba found in warm freshwater, infecting humans through nasal passages during water-related activities.
• Current treatments for PAM are largely ineffective, with a mortality rate exceeding 90%.

Purpose of the Study:

• To evaluate the in vitro efficacy of novel naphthyridine-fused chromene/chromenone compounds against Naegleria fowleri.
• To investigate the mechanism of action of the most potent compound, specifically its ability to induce programmed cell death (PCD) in Naegleria fowleri.

Main Methods:

• Synthesis of naphthyridine-fused chromene or chromenone compounds.
• In vitro testing of compounds against trophozoite stages of two Naegleria fowleri strains (ATCC® 30808 and ATCC® 30215).
• Evaluation of compound-induced programmed cell death, including DNA condensation, membrane damage, mitochondrial potential, ATP levels, and ROS generation.

Main Results:

• Compound 3 demonstrated significant anti-Naegleria activity with IC50 values of 61.45 ± 5.27 µM and 76.61 ± 10.84 µM against the tested strains.
• Compound 3 exhibited good selectivity, with cytotoxicity values greater than 300 µM.
• The compound successfully induced PCD in Naegleria fowleri, evidenced by DNA condensation, membrane damage, reduced mitochondrial membrane potential and ATP levels, and increased ROS generation.

Conclusions:

• Naphthyridine-fused chromenes or chromenones, particularly compound 3, show potential as therapeutic agents against Naegleria fowleri.
• Compound 3's ability to induce PCD provides a mechanistic basis for its anti-amoebic activity.
• Further research into these compounds could lead to novel treatments for primary amoebic encephalitis.