Dillapiole as antileishmanial agent: Discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues

Parise-Filho R.; Pasqualoto K.F.M.; Magri F.M.M.; Ferreira A.K.; Da Silva B.A.V.G.; Damiao M.C.F.C.B.; Tavares M.T.; Azevedo R.A.; Auada A.V.V.; Polli M.C.; Brandt C.A.

Dillapiole as antileishmanial agent: Discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues

Tipo

Artigo

Data de publicação

2012

Periódico

Archiv der Pharmazie

Citações (Scopus)

33

Autores

Parise-Filho R.
Pasqualoto K.F.M.
Magri F.M.M.
Ferreira A.K.
Da Silva B.A.V.G.
Damiao M.C.F.C.B.
Tavares M.T.
Azevedo R.A.
Auada A.V.V.
Polli M.C.
Brandt C.A.

Resumo

In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC 50 = 69.3 μM) and Leishmania brasiliensis (IC50 = 59.4 μM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC50 = 99.9 μM for L. amazonensis and IC50 = 90.5 μM for L. braziliensis) and 3 (IC50 = 122.9 μM for L. amazonensis and IC50 = 109.8 μM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues. Dillapiole (1) presented relevant effects against Leishmania amazonensis and L. brasiliensis. Additionally, compound 1 reduced fibroblast cell viability, indicating that this compound might have antileishmanial effects on non-phagocytic cells in the latent phase of the disease. SAR studies showed that the conformational arrangement and electronic properties as well as the hydro/lipophilic balance seem to be crucial for antileishmanial activity. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.