We describe herein the antitrypanosomal activity of 20 novel 1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory concentrationvalues in the range of 6-18 µM. In the cytotoxicity tests against L929 cells, only compound 4 presented selectivity index value above 10, indicating low toxicity.

Annona cornifolia A. St. -Hil. é uma pequena árvore anual perene encontrada no cerrado brasileiro; seu fruto verde é usado popularmente no tratamento de úlceras. As acetogeninas isoladas a partir das sementes de Annona cornifolia anteriormente apresentaram atividade antioxidante. Continuando as nossas investigações sobre as atividades biológicas das acetogeninas, quatro misturas binárias e dez acetogeninas bis-tetra-hidrofurânicas adjacentes puras foram avaliadas quanto às atividades: citotóxica (sobre três linhagens de células tumorais humanas), antifúngica (sobre Paracoccidioides brasiliensis), tripanocida (sobre Trypanosoma cruzi) e leishmanicida (sobre Leishmania amazonensis). As acetogeninas apresentaram atividade citotóxica, confirmando seu uso potencial na terapia anticâncer. Quanto às atividades leishmanicida e tripanocida, foi observada uma inibição de 87% das formas amastigotas de L. amazonensis e 100% de formas amastigotas e tripomastigotas de T. cruzi, quando testadas a uma concentração de 20 µg mL–1. Além disso, seis acetogeninas mostraram maior atividade sobre todas as três cepas testadas de P. brasiliensis que o trimetoprim-sulfametoxazol, um medicamento usado no tratamento da paracoccidioidomicose. Assim, as acetogeninas podem ser uma alternativa no tratamento de uma série de doenças que têm um enorme impacto em milhões de pessoas no mundo. Este trabalho relata pela primeira as atividades antifúngica, leishmanicida e tripanocida para estas acetogeninas.

Annona cornifolia A. St. -Hil. is a small annual perennial tree found in the Brazilian savannah; their green fruit is popularly used in the treatment of ulcers. The acetogenins isolated from the seeds of Annona cornifolia previously showed to possess antioxidant activity. In continuation of our investigations on the biological activities of acetogenins, four binary mixtures and ten pure adjacent bis-tetrahydrofuran annonaceous acetogenins were evaluated: the cytotoxic (against three human tumor cell lines), antifungal (against Paracoccidioides brasiliensis), trypanocidal (against Trypanosoma cruzi) and leishmanicidal (against Leishmania amazonensis) activities. Acetogenins presented cytotoxic activity confirming their potential use in anti-cancer therapy. Regarding leishmanicidal and trypanocidal activities, an inhibition of 87% of L. amazonensis amastigotes and 100% of T. cruzi amastigotes and trypomastigotes was observed, when tested at the concentration of 20 µg mL–1. Moreover, six acetogenins showed more activity against all the three tested isolates of P. brasiliensis than trimethoprim-sulfamethoxazole, a drug used for treating paracoccidioidomycosis. Thus, acetogenins may be an alternative in treating a number of diseases that have a huge impact on millions of people worldwide. This paper reports for the first time the antifungal, leishmanicidal and trypanocidal activities for these acetogenins.

Four diamines and three amino alcohols derived from 1-decanol, 1-dodecanol and 1,2-dodecanediol were evaluated in an in vitro assay against a mixture of trypomastigote and intracellular amastigote forms of Trypanosoma cruzi. Two of these compounds (6 and 7) showed better activity against both proliferative stages of T. cruzi than the positive control benznidazole, three were of similar potency (1, 2 and 5) and two were less active (3 and 4).

Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of heart failure. We investigated modifications in the cellular electrophysiological and calcium-handling characteristics of an infected mouse heart during the chronic phase of the disease. The patch-clamp technique was used to record action potentials (APs) and L-type Ca2+ and transient outward K+ currents. [Ca2+]i changes were determined using confocal microscopy. Infected ventricular cells showed prolonged APs, reduced transient outward K+ and L-type Ca2+ currents and reduced Ca2+ release from the sarcoplasmic reticulum. Thus, the chronic phase of Chagas disease is characterised by cardiomyocyte dysfunction, which could lead to heart failure.

In this study we prepared an inclusion complex between an iodide analogue of metronidazole (MTZ-I) and cyclodextrin (CD) to develop a safer and more effective method of treating Trypanosoma cruzi infections. According to our results, MTZ-I and MTZ-I:β-CD were 10 times more active than MTZ, demonstrating that the presence of an iodine atom on the side chain increased the trypanocidal activity while maintaining its cytotoxicity. The selective index shows that MTZ-I was 10 times more active against T. cruzi than it was against mammalian cells. The modification of MTZ side chains provides a promising avenue for the development of new drugs.