Synthesis of 3,5-Diarylisoxazole Derivatives and Evaluation of in vitro Trypanocidal Activity

Abstract

Chagas disease is included in the neglected tropical diseases list and is endemic to 21 Latin American countries. The two drugs currently available for treating Chagas disease are nifurtimox and benznidazole and both result in many significant side effects. The study describes the synthesis and biological evaluation of 3,5-disubstituted isoxazoles. Isoxazoles were obtained by reaction of flavones and hydroxylamine and either alkylated at the free hydroxyl group and/or nitrated at the isoxazole ring. These compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against trypomastigote and amastigote forms of the parasite in T. cruzi-infected cell lineages. Benznidazole was used as a reference compound for the in vitro assay and mammalian L929 cells were employed to evaluate cytotoxicity. A majority of the compounds tested were very active and the most active isoxazole against amastigote and trypomastigotes of T. cruzi was slightly more potent than the current medicine benznidazole.

Synthesis, photophysical and electrochemical properties of novel and highly fluorescent difluoroboron flavanone β-diketonate complexes

“…Esters 1a-e were subjected to a Baker-Venkataraman rearrangement in the second step to afford diketones 2a-e in excellent yields (Scheme 1). 18,19 All the synthetized b-diketones are known compounds in the literature and therefore were confirmed by comparison of their physical and spectroscopy data with the reported data in the literature (see Experimental section).…”

Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi

“…The use of the epimastigote form present in the midgut vector can be employed for an in vitro screening method (Menezes et al, 2014;Moreira et al, 2014) but we have opted for a methodology that simultaneously evaluates trypomastigote forms that are initially present in the blood after entering through the bite wound and intracellular amastigotes forms present in the vertebrate host during the acute and chronic phases of the disease (de Souza et al, 2018;Elias et al, 2016). There have been different approaches taken toward the in vitro evaluation of anti-T. cruzi activity.…”

“…The use of the epimastigote form present in the midgut vector can be employed for an in vitro screening method (Menezes et al, 2014;Moreira et al, 2014) but we have opted for a methodology that simultaneously evaluates trypomastigote forms that are initially present in the blood after entering through the bite wound and intracellular amastigotes forms present in the vertebrate host during the acute and chronic phases of the disease (de Souza et al, 2018;Elias et al, 2016). This approach is in accordance with the guidelines proposed by the Fiocruz Program for Research and Technological Development on Chagas Disease and the Drugs for Neglected Diseases Initiative (DNDi) (de Souza et al, 2018;Elias et al, 2016). Furthermore, the whole cell-based screening methodology is also attractive given that bioactive compounds can be tested for anti-T. cruzi activity in infected cells while at the same time monitoring their effects on both amastigotes and trypomastigotes in the same system.…”

Trypanocidal Activity of Flavanone Derivatives

“…Flavanone derivatives were evaluated for anti-T. cruzi activity against the intracellular forms of the parasite. Although the use of epimastigotes present in the midgut vector may be utilized for initial screening [19,20], we have instead opted for the simultaneous use of trypomastigote and intracellular amastigotes forms that are present during both acute and chronic phases of the disease [21,22]. This approach is in accordance with the Drugs for Neglected Diseases Initiative guidelines (DNDi) [23].…”