Antiparasitic Derivatives of the Furoquinoline Alkaloids Kokusaginine And Flindersiamine

BELÉN VALDEZ, MARÍA; BERNAL GIMÉNEZ, DIANA MARÍA; FERNÁNDEZ, LUCÍA RAQUEL; MUSIKANT, ALEJANDRO DANIEL; FERRI, GABRIEL; SÁENZ, DANIEL; DI VENOSA, GABRIELA; CASAS, ADRIANA; AVIGLIANO, ESTEBAN; EDREIRA, MARTÍN MIGUEL; PALERMO, JORGE ALEJANDRO

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

Año: 2022 vol. 17 p. 1 - 9

1860-7179

We report 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 C4 position 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 1 c and 1 e displayed better in-vitro activity against trypomastigotes than benznidazole and nifurtimox (positive controls) with IC50<4 μM. In addition, both compounds were not cytotoxic against the three human cell lines K562 (erytroleukimia), LM2 (breast cancer), and HaCat (keratinocyte). Interestingly, when evaluated against intracellular amastigotes, compound 1 c was able to significantly reduce the number of this parasite form, compared to the negative control.