New antiparasitic derivatives of the furoquinoline alkaloids kokusaginine and flindersiamine

VALDEZ, MARÍA BELÉN; BERNAL, DIANA; FERNÁNDEZ, LUCÍA R.; MUSIKANT, DANIEL; FERRI, GABRIEL; SAENZ, DANIEL; DI VENOSA, GABRIELA M.; CASAS, ADRIANA G.; AVIGLIANO, ESTEBAN; EDREIRA, M.; PALERMO, J.A.

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2022

1860-7179

In this work is reported the synthesis of 16 new compounds obtained from kokusaginine and flindersiamine, the main alkaloids isolated from the bark of Balfourodendron riedelianum. The activity of the compounds against axenic cultures of Trypanosoma cruzi epimastigtotes and trypomastigotes, as well as intracellular amastigotes, is described, together with their cytotoxic activity against three different human cell lines. The synthetic strategy for the preparation of the new compounds was based on the reactivity at the position C-4 of the furoquinoline core towards nucleophiles. The new derivatives were synthesized by a Buchwald-Hartwig reaction, in most cases under green, solvent free conditions. Compounds 1c and 1e displayed better in-vitro activity against trypomastigotes than benznidazole and nifurtimox (positive controls) with IC50 < 4 µM. In addition, both compounds were not cytotoxic activity against the three human cell lines K562 (erytroleukimia), LM2 (breast cancer) and HaCat (keratinocyte). Interestingly, when evaluated against intracellular amastigotes, compound 1c was able to significantly reduce the number of this parasite form, compared to the negative control.