title: Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues.
abstract: 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 (IC(50)  = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50)  = 99.9 µM for L. amazonensis and IC(50)  = 90.5 µM for L. braziliensis) and 3 (IC(50)  = 122.9 µM for L. amazonensis and IC(50)  = 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Department of Pharmacy, University of São Paulo, 05508-900 São Paulo, Brazil. roberto.parise@usp.br
authors.forename: Roberto
authors.initials: R
authors.lastname: Parise-Filho
authors.forename: Kerly Fernanda Mesquita
authors.initials: KF
authors.lastname: Pasqualoto
authors.forename: Fátima Maria Motter
authors.initials: FM
authors.lastname: Magri
authors.forename: Adilson Kleber
authors.initials: AK
authors.lastname: Ferreira
authors.forename: Bárbara Athayde Vaz Galvão
authors.initials: BA
authors.lastname: da Silva
authors.forename: Mariana Celestina Frojuello Costa Bernstorff
authors.initials: MC
authors.lastname: Damião
authors.forename: Maurício Temotheo
authors.initials: MT
authors.lastname: Tavares
authors.forename: Ricardo Alexandre
authors.initials: RA
authors.lastname: Azevedo
authors.forename: Aline Vivian Vatti
authors.initials: AV
authors.lastname: Auada
authors.forename: Michelle Carneiro
authors.initials: MC
authors.lastname: Polli
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Brandt
mesh_terms: D016475:3T3 Cells; D000498:Allyl Compounds / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004149:Dioxoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D007536:Isomerism; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D031701:Piper / Q000737:chemistry; D018515:Plant Leaves / Q000737:chemistry; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000498:Allyl Compounds; D004149:Dioxoles; D014344:Trypanocidal Agents; C498255:5-allyl 6,7-dimethoxy 1,3-benzodioxole