Synthesis, antileishmanial activity and spin labeling EPR studies of novel β-carboline-oxazoline and β-carboline-dihydrooxazine derivatives

Resumo

A series of novel 1-(substituted-phenyl)-3-(4,5-dihydro-1,3-oxazol-2-yl)-9H-β-carboline (8a-8i) and 1-(substituted-phenyl)-3-(5,6-dihydro-4H-1,3-oxazin-2-yl)-9H-β-carboline (9a-9h) derivatives, as well as their respective N-(chloroalkyl)-1-(substituted-phenyl)-9H-β-carboline-3-carboxamide precursors (6a-6i and 7a-7h), were synthesized and evaluated for their in vitro antileishmanial activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. Compounds 8d, 8i, 9e and 9h exhibited significant activity for both promastigote and amastigote forms, with IC50 (50% inhibitory concentration) values ranging from 2.9 to 23.0 μM. In addition, spin label electron paramagnetic resonance (EPR) spectroscopy studies were carried out for the most active compounds against L. amazonensis promastigotes. The studies indicated that the tested compounds cause strong stiffness in the parasite plasma membrane and are capable of inducing internal metalloproteins oxidation of the parasite, resulting in their cross-linking to skeletal proteins. Compounds 8d and 8i produced the largest effect, showing that the presence of oxazoline group at C-3 of β-carboline nucleus is important for antileishmanial activity.

Descrição

Palavras-chave

β-carboline, 4,5-dihydro-1,3-oxazole, 5,6-dihydro-4H-1,3-oxazine, Electron paramagnetic resonance, Leishmania amazonensis

Citação

BARÉA, Paula; PAULA, Jéssica C. de; ALONSO, Laís; OLIVEIRA, Aline R. de; COSTA, Willian F. da; Alonso, Antonio; NAKAMURA, Celso V.; SARRAGIOTTO, Maria H. Synthesis, antileishmanial activity and spin labeling EPR studies of novel β-carboline-oxazoline and β-carboline-dihydrooxazine derivatives. Journal of the Brazilian Chemical Society, Campinas, v. 31, n. 6, p. , 1170-1185, 2020. Disponível em: https://s3.sa-east-1.amazonaws.com/static.sites.sbq.org.br/jbcs.sbq.org.br/pdf/2019-0581AR.pdf. Acesso em: 14 abr. 2023.