Antitrypanosomal activity of isololiolide isolated from the marine hydroid Macrorhynchia philippina (Cnidaria, Hydrozoa)

• Published in: Bioorganic chemistry Vol. 89; p. 103002
• Main Authors: Lima, Marta L., Romanelli, Maiara M., Borborema, Samanta E.T., Johns, Deidre M., Migotto, Alvaro Esteves, Lago, João Henrique G., Tempone, Andre G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2019
• Subjects: Isololiolide; Macrorhynchia philippina; Marine invertebrate; Mechanism of action; Stinging hydroid; Therapy; Trypanosoma cruzi; Marine invertebrate; Therapy; Isololiolide; Stinging hydroid; Macrorhynchia philippina; Mechanism of action; Trypanosoma cruzi
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103002

[Display omitted] •The novel occurrence of the isololiolide was described in a marine cnidarian, Macrorhynchia philippina.•Isololiolide exhibited anti-T. cruzi activity and no mammalian cytotoxicity.•Isololiolide depolarized the mitochondrial membrane potential of T. cruzi.•Isololiolide induced permeabilization of the plasma membrane of T. cruzi.•Isololiolide induced lethal mechanisms in T. cruzi. Marine invertebrates are a rich source of small antiparasitic compounds. Among them, Macrorhynchia philippina is a chemically underexplored marine cnidarian. In the search for candidates against the neglected protozoan Chagas disease, we performed a bio-guided fractionation to obtain active compounds. The structural characterization of the active compound was determined using NMR analysis and MS and resulted in the isololiolide, a compound described for the first time in this species. It showed in vitro activity against both trypomastigote and intracellular amastigotes of Trypanosoma cruzi, with IC50 values of 32 µM and 40 µM, respectively, with no mammalian cytotoxicity (>200 µM). The lethal action was investigated in T. cruzi using different fluorophores to study: (i) mitochondrial membrane potential; (ii) plasma membrane potential and (iii) plasma membrane permeability. Our results demonstrated that isololiolide caused disruption of the plasma membrane integrity and a strong depolarization of the mitochondrial membrane potential, rapidly leading the parasite to death. Despite being considered a possible covalent inhibitor, safety in silico studies of isololiolide also considered neither mutagenic nor genotoxic potential. Additionally, isololiolide showed no resemblance to interference compounds (PAINS), and it succeeded in most filters for drug-likeness. Isololiolide is a promising candidate for future optimization against Chagas disease.