Isobenzofuranones: new therapeutic agents against amoeba Acanthamoeba castellanii Neff.

The amoebas of the genus Acanthamoeba are opportunistic parasitic protozoa belonging to the group of free-living amoebas that have a cosmopolitan distribution. They have been isolated from samples of soil, dust, air, natural and treated freshwater, seawater, swimming pools, sewage, sediment, air conditioning, hospitals, contact lenses, and cell cultures. They have also been isolated from the plant and animal kingdoms (fish, amphibians, reptiles, and mammals), as well as from the nasopharyngeal cavity of apparently healthy people and immunocompromised patients. Their life cycle involves two phases: an active phase called the trophozoite, and a dormant phase known as the cyst. The most common infections caused by these parasites are inflammation of the cornea of the eye (severe keratitis) in healthy individuals (particularly contact lens wearers) and chronic and fatal granulomatous amoebic meningoencephalitis. The existence of the cyst phase, the dormant and resistant phase, endows these parasites with great resistance to their full eradication from infected tissues. The lack of effective and well-established treatments in the current pharmacopoeia for the total recovery of the infected patient is a social demand that requires a pharmacological response.

In this line, the research teams of the Instituto de Productos Naturales y Agrobiología (IPNA-CSIC) (Drs. Tejedor Aragón and García Tellado, Department of Molecular Sciences, 'Structure, design and molecular function' research group) and the Instituto de Enfermedades Tropicales y Salud Pública de Canarias (ULL) led by doctors Lorenzo-Morales and Piñero Barroso, are developing a research program focused on the search for new chemotypes with antiamoebic activity. Within the chemotypes tested, some members of a small library focused on the isobenzofuranone core (see figure) were particularly effective against the amoeba Naegleria fowleri1. With this precedent, the library was tested against four lines of Acanthamoeba in search of new antiamebic annotations. Although all the members of the chemical library (QOET1-10) showed some anti-Acanthamoeba activity with different degrees of cytotoxicity, the isobenzofuranones QOET-3 and QOET-9 were especially active against the two states or phases of the Acanthamoeba lines tested, and were especially active against Acanthameba castellanii Neff, inducing programmed cell death. The results obtained in this study expand the pharmacological space of isobenzofuranones, opening new frontiers for the development of new amebicide drugs based on this chemotype.


This work has been published in the open access journal International Biomedicine & Pharmacotherapy.

Rubén L. Rodríguez-Expósito, María Reyes-Batlle, Ines Sifaoui, D. Tejedor, F. García-Tellado, J. E. Piñero, J. Lorenzo-Morales. Isobenzofuran-1(3H)-one derivatives: Amoebicidal activity and program cell death in Acanthamoeba castellanii Neff. Biomed. Pharmacother. 2022, 150, 113062.

1A. Rizo-Liendo, I. Arberas-Jiménez, I. Sifaoui, D. Gkolfi, Y. Santana, L. Cotos, D. Tejedor, F. García-Tellado, J. E. Piñero, J. Lorenzo-Morales. The therapeutic potential of novel isobenzofuranones against Naegleria fowleri. Int. J. Parasitol-Drug 2021, 17, 139-149.


Acanthamoeba castellanii