Cyclolauranes as plausible chemical scaffold against Naegleria fowleri

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.

A.R.L. and I.A.J. acknowledge funding from Agencia Canaria de Investigación, Innovación y Sociedad de la Información (ACIISI). S.G.-D. (grant 740689) thank Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico, for a postdoctoral fellowship. Authors acknowledge Dr. R. Riosmena Rodríguez (Universidad Autónoma de Baja California Sur, UABCS) for identification of the algae. This study was supported by the Ministry of Science and Innovation, Spain (project no. PID2019-109476RB-C21, BIOALGRI); the Red de Investigación Cooperativa en Enfermedades Tropicales (RICET), Spain (project no. RD16/0027/0001 of the programe of Redes Temáticas de Investigación Cooperativa, FIS), Consorcio Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain (CB21/13/00100), Ministerio de Sanidad, Gobierno de España and by the project No. 21/0587 funded by the ‘Cabildo de Tenerife, Tenerife innova, Marco Estratégico de Desarrollo Insular (MEDI) and Fondo de Desarrollo de Canarias (FDCAN).

Peer reviewed