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Published on: July 17, 2020
Cyclolauranes as plausible chemical scaffold against Naegleria fowleri
Iñigo Arberas-Jiménez1, Sara García-Davis2, Aitor Rizo-Liendo1
1Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), Universidad de La Laguna (ULL), Avenida Astrofísico Francisco Sánchez s/n, 38206 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 (ULL), Tenerife, Spain; Red de Investigación Cooperativa en Enfermedades Tropicales (RICET), Spain.
Abstract:
Primary amoebic meningoencephalitis (PAM) is a central nervous system (CNS) disease caused by Naegleria fowleri that mainly affects children and young adults with fatal consequences in most of the cases. Treatment protocols are based on the combination of different antimicrobial agents, nonetheless there is the need to develop new anti-Naegleria compounds with low toxicity and full effects compared to the currently used drug combination. The marine environment is a well-established source of bioactive natural products. In this work, we have focused on the structure of Laurencia cyclolaurane-type sesquiterpenes as potential chemical model against Naegleria species. The effects of debromolaurinterol (1) to induce PCD/apoptosis-like events in Naegleria fowleri have been evaluated, revealing that this compound induced reduction of ATP production showing a decrease of 99.98% in treated parasite cells. A SAR analysis have been supported with molecular modeling and analysis of the in silico ADME/Tox properties of the Laurencia sesquiterpenes debromolaurinterol (1), laurinterol (2) and allolaurinterol (3), which reinforce cyclolaurane metabolites as plausible molecular models to develop PAM treatments.
Insights
Marine natural products show promise for treating primary amoebic meningoencephalitis (PAM). Debromolaurinterol effectively reduced ATP production in Naegleria fowleri, suggesting potential for new PAM therapies.
Area of Science:
- Marine natural product chemistry
- Parasitology
- Drug discovery
Background:
- Primary amoebic meningoencephalitis (PAM) is a fatal CNS infection caused by Naegleria fowleri, primarily affecting young individuals.
- Current treatment protocols for PAM require novel compounds with improved efficacy and reduced toxicity.
- Marine organisms, particularly Laurencia species, are rich sources of diverse bioactive compounds.
Purpose of the Study:
- To investigate Laurencia cyclolaurane-type sesquiterpenes as potential therapeutic agents against Naegleria species.
- To evaluate the anti-Naegleria activity of debromolaurinterol and related compounds.
- To explore structure-activity relationships (SAR) and in silico properties for drug development.
Main Methods:
- Screening of Laurencia sesquiterpenes for anti-Naegleria activity.
- Assessment of debromolaurinterol's effect on Naegleria fowleri ATP production.
- Structure-activity relationship (SAR) analysis.
- In silico molecular modeling and ADME/Tox property prediction.
Main Results:
- Debromolaurinterol induced significant cell death in Naegleria fowleri, reducing ATP production by 99.98%.
- SAR analysis and in silico studies supported the potential of cyclolaurane metabolites as PAM drug leads.
- Debromolaurinterol, laurinterol, and allolaurinterol exhibited varying degrees of anti-Naegleria activity.
Conclusions:
- Laurencia sesquiterpenes, particularly debromolaurinterol, demonstrate potent activity against Naegleria fowleri.
- These marine natural products represent promising molecular models for developing novel treatments for primary amoebic meningoencephalitis.
- Further research into cyclolaurane derivatives could lead to effective and low-toxicity PAM therapies.
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