Sesquiterpene lactones as potential therapeutic agents against Naegleria fowleri

Naegleria fowleri is the causative agent the primary amoebic meningoencephalitis (PAM), a fatal disease in more than the 90% of the reported cases that affects the central nervous system. The amoeba infects the nasal cavity of mostly children and young adults who report previous aquatic exposure in warm water sources. The rapid progression of the disease and the lack of effective and safety therapeutic options make the search of new anti-amoebic compounds an urgent issue. In this study, twelve sesquiterpene lactones isolated from the zoanthid Palythoa aff. clavata were tested against the trophozoite stage of Naegleria fowleri. Anhydroartemorin (2) and 1(10)Z,4E,14-acetoxy-costunolide (3) showed the best anti-amoeboid activity values with IC50 23.02 ± 1.26 and 28.34 ± 6.27, respectively. In addition, the mechanisms of programmed cell death induction of these two molecules were evaluated with positive results for both compounds. Finally, a structure-activity relationship was analyzed to reveal the dependence of reactivity and lipophilicity on the biological activity. The log P values of the compounds were calculated to postulate them as good candidates to cross the blood-brain barrier, a limiting factor in the development of new anti-Naegleria treatments. Therefore, the mentioned sesquiterpene lactones could be considered as potential PAM therapeutic options in the future.This work was funded by projects PI18/01380 from Instituto de Salud Carlos III, Spain and RICET (RD16/0027/0001 project) and PID2019–109476RB-C21 (BIOALGRI) (Spanish Ministry of Science, Madrid, Spain; from Programa Redes Temáticas de Investigación Cooperativa, FIS (Ministerio Español de Salud, Madrid, Spain) and FEDER. Consorcio Centro de Investigación Biomédica En Red M.P. (CIBER) de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28006 Madrid, Spain and Cabildo de Tenerife 21/0587 cofunded by MEDI and FDCAN. ARL and IAJ were funded by Agencia Canaria de Investigación, Innovación y Sociedad de la Información (ACIISI). N.N. were funded by the Agustín de Betancourt Programme (Cabildo de Tenerife, TFinnova Programme supported by MEDI and FDCAN funds). Authors acknowledge to Drs. Alberto Brito and Adriana Rodríguez Hernández from Universidad de La Laguna (ULL) the taxonomic classification of biological material, and Dr. Ezequiel Quintana Morales from Instituto de Productos Naturales y Agrobiología, Consejo Superior de Investigaciones Científicas (IPNA-CSIC) for assistance in molecular calculations.Peer reviewe

Cyanomethyl Vinyl Ethers Against Naegleria fowleri

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.This work was funded by the Consorcio Centro de Investigación Biomédica (CIBER) de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28006 Madrid, Spain, Cabildo Insular de Tenerife 2023-2028 and Ministerio de Sanidad, Spain. IAJ (TESIS202001063) was funded by the Agencia Canaria de Investigación, Innovación y Sociedad de la Información (ACIISI). Grant PID2021-128047NB-I00, funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. Grant PDC2022-133706-I00, funded by MCIN/AEI /10.13039/501100011033 and by the “European Union NextGenerationEU/PRTR”.Peer reviewe

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 reviewe