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Cyanomethyl Vinyl Ethers Against Naegleria fowleri
Javier Chao-Pellicer1,2,3, Iñigo Arberas-Jiménez1,2, Samuel Delgado-Hernández4,5
1Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Avda. Astrofísico Fco. Sánchez, S/N, La Laguna 38203, Tenerife, Islas Canarias, Spain.
Abstract:
Naegleria fowleri is a pathogenic amoeba that causes a fulminant and rapidly progressive disease affecting the central nervous system called primary amoebic meningoencephalitis (PAM). Moreover, the disease is fatal in more than 97% of the reported cases, mostly affecting children and young people after practicing aquatic activities in nontreated fresh and warm water bodies contaminated with these amoebae. Currently, the treatment of primary amoebic meningoencephalitis is based on a combination of different antibiotics and antifungals, which are not entirely effective and lead to numerous side effects. In the recent years, research against PAM is focused on the search of novel, less toxic, and fully effective antiamoebic agents. Previous studies have reported the activity of cyano-substituted molecules in different protozoa. Therefore, the activity of 46 novel synthetic cyanomethyl vinyl ethers (QOET-51 to QOET-96) against two type strains of N. fowleri (ATCC 30808 and ATCC 30215) was determined. The data showed that QOET-51, QOET-59, QOET-64, QOET-67, QOET-72, QOET-77, and QOET-79 were the most active molecules. In fact, the selectivity index (CC50/IC50) was sixfold higher when compared to the activities of the drugs of reference. In addition, the mechanism of action of these compounds was studied, with the aim to demonstrate the induction of a programmed cell death process in N. fowleri.
Insights
Novel cyanomethyl vinyl ethers show promise against Naegleria fowleri, the cause of deadly primary amoebic meningoencephalitis (PAM). These compounds offer a potentially safer and more effective treatment for this devastating infection.
Area of Science:
- Infectious Diseases
- Parasitology
- Medicinal Chemistry
Background:
- Naegleria fowleri causes primary amoebic meningoencephalitis (PAM), a rare but almost universally fatal central nervous system infection.
- Current PAM treatments are often ineffective and associated with significant side effects, necessitating the development of novel therapeutic agents.
- Previous research indicated the antiprotozoal potential of cyano-substituted compounds.
Purpose of the Study:
- To evaluate the efficacy of novel synthetic cyanomethyl vinyl ethers against Naegleria fowleri.
- To identify potent antiamoebic agents with improved selectivity compared to existing treatments.
- To investigate the mechanism of action of the most active compounds.
Main Methods:
- Synthesis and screening of 46 novel cyanomethyl vinyl ethers (QOET-51 to QOET-96) against Naegleria fowleri type strains (ATCC 30808 and ATCC 30215).
- Determination of inhibitory concentrations (IC50) and cytotoxicity (CC50) to calculate selectivity indices.
- Exploration of the mechanism of action, focusing on the induction of programmed cell death.
Main Results:
- Seven compounds (QOET-51, QOET-59, QOET-64, QOET-67, QOET-72, QOET-77, and QOET-79) demonstrated significant antiamoebic activity.
- The most active compounds exhibited a sixfold higher selectivity index compared to reference drugs.
- Evidence suggests these compounds induce programmed cell death in Naegleria fowleri.
Conclusions:
- Novel cyanomethyl vinyl ethers represent a promising class of compounds for the development of new treatments against Naegleria fowleri.
- The identified compounds offer a potentially safer therapeutic alternative due to their enhanced selectivity.
- Further research into their mechanism of action could lead to targeted therapies for primary amoebic meningoencephalitis.
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