title: Immunomodulatory and Antileishmanial Activity of Phenylpropanoid Dimers Isolated from Nectandra leucantha.
abstract: Three phenylpropanoid dimers (1-3) including two new metabolites were isolated from the extract of the twigs of Nectandra leucantha using antileishmanial bioassay-guided fractionation. The in vitro antiparasitic activity of the isolated compounds against Leishmania donovani parasites and mammalian cytotoxicity and immunomodulatory effects were evaluated. Compounds 1-3 were effective against the intracellular amastigotes within macrophages, with IC50 values of 26.7, 17.8, and 101.9 μM, respectively. The mammalian cytotoxicity, given by the 50% cytotoxic concentration (CC50), was evaluated against peritoneal macrophages. Compounds 1 and 3 were not toxic up to 290 μM, whereas compound 2 demonstrated a CC50 value of 111.2 μM. Compounds 1-3 also suppressed production of disease exacerbatory cytokines IL-6 and IL-10 but had minimal effect on nitric oxide production in L. donovani-infected macrophages, indicating that antileishmanial activity of these compounds is mediated via an NO-independent mechanism. Therefore, these new natural products could represent promising scaffolds for drug design studies for leishmaniasis.
authors.affiliation: †Center for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, Brazil.
authors.forename: Thais Alves
authors.initials: TA
authors.lastname: da Costa-Silva
authors.affiliation: ‡Center of Natural Sciences and Humanities, Federal University of ABC, São Paulo, Brazil.
authors.forename: Simone S
authors.initials: SS
authors.lastname: Grecco
authors.affiliation: §Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: de Sousa
authors.affiliation: §Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: João Henrique G
authors.initials: JH
authors.lastname: Lago
authors.affiliation: ⊥Department of Botany, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Euder G A
authors.initials: EG
authors.lastname: Martins
authors.affiliation: ∥Departments of Pathology and Microbiology, Ohio State University, Columbus, Ohio, United States.
authors.forename: César A
authors.initials: CA
authors.lastname: Terrazas
authors.affiliation: ∥Departments of Pathology and Microbiology, Ohio State University, Columbus, Ohio, United States.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Varikuti
authors.affiliation: ∇Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Owens
authors.affiliation: ∇Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Beverley
authors.affiliation: ∥Departments of Pathology and Microbiology, Ohio State University, Columbus, Ohio, United States.
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.affiliation: †Center for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, Brazil.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Tempone
mesh_terms: D000818:Animals; D000840:Anisoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001938:Brazil; D007155:Immunologic Factors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D016753:Interleukin-10; D015850:Interleukin-6; D019770:Lauraceae / Q000737:chemistry*; D007893:Leishmania donovani / Q000187:drug effects; D007896:Leishmaniasis / Q000188:drug therapy*; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D010666:Phenylpropionates / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D018547:Plant Stems / Q000737:chemistry
chemical_list: C000600759:1-(7R-hydroxy-8-propenyl)-3-(3'-methoxy-1'-(8'-propenyl)phenoxy)-4-hydroxy-5-methoxybenzene; D000840:Anisoles; D000981:Antiprotozoal Agents; D007155:Immunologic Factors; D015850:Interleukin-6; D010666:Phenylpropionates; C000600757:dehydrodieugenol B; D016753:Interleukin-10; D009569:Nitric Oxide
references.citation: J Pharm Pharmacol. 2004 Sep;56(9):1195-9
references.pmid: 15324490
references.citation: Parasitol Res. 2007 Mar;100(4):791-5
references.pmid: 17053932
references.citation: Phytother Res. 2008 Oct;22(10):1307-10
references.pmid: 18688887
references.citation: Clin Infect Dis. 2013 Jun;56(11):1530-8
references.pmid: 23425958
references.citation: Molecules. 2009;14(7):2317-36
references.pmid: 19633606
references.citation: Immunol Cell Biol. 2008 Aug-Sep;86(6):539-43
references.pmid: 18542100
references.citation: Front Immunol. 2014 Jun 26;5:296
references.pmid: 25183962
references.citation: Vet Immunol Immunopathol. 2007 Jan 15;115(1-2):135-45
references.pmid: 17097741
references.citation: J Nat Prod. 2012 Mar 23;75(3):311-35
references.pmid: 22316239
references.citation: Arch Pharm Res. 2012 Feb;35(2):315-20
references.pmid: 22370785
references.citation: Planta Med. 2006 Dec;72(15):1396-402
references.pmid: 17089325
references.citation: J Nat Prod. 2002 Dec;65(12):1754-8
references.pmid: 12502308
references.citation: Planta Med. 1999 Aug;65(6):541-4
references.pmid: 10483375
references.citation: Clin Immunol. 2006 Jun;119(3):339-45
references.pmid: 16540374
references.citation: Methods. 2007 Aug;42(4):377-87
references.pmid: 17560325
references.citation: Clin Infect Dis. 2000 Oct;31(4):1110-3
references.pmid: 11049800
references.citation: Nat Prod Commun. 2014 Feb;9(2):171-3
references.pmid: 24689283
references.citation: Parasitology. 2011 Sep;138(10):1224-33
references.pmid: 21810308
references.citation: J Ethnopharmacol. 2005 Mar 21;97(3):561-6
references.pmid: 15740896
references.citation: Phytother Res. 2004 Mar;18(3):250-4
references.pmid: 15103676
references.citation: Clin Microbiol Infect. 2011 Oct;17(10):1471-7
references.pmid: 21933305
references.citation: J Immunol Methods. 1986 Nov 6;93(2):157-65
references.pmid: 3490518
references.citation: PLoS Pathog. 2008 Nov;4(11):e1000222
references.pmid: 19043558
references.citation: Bioorg Med Chem Lett. 2005 Jan 17;15(2):303-7
references.pmid: 15603944
references.citation: Am J Trop Med Hyg. 2007 Apr;76(4):669-75
references.pmid: 17426168
references.citation: J Med Chem. 2013 Jun 13;56(11):4374-92
references.pmid: 23611626
references.citation: Curr Med Chem. 2012;19(25):4259-88
references.pmid: 22834813
references.citation: Biol Pharm Bull. 2012;35(10):1761-4
references.pmid: 23037165
references.citation: Exp Parasitol. 2010 Mar;124(3):319-24
references.pmid: 19944690
references.citation: Phytochemistry. 2008 Jan;69(2):445-50
references.pmid: 17888465
references.citation: Infect Immun. 2008 Sep;76(9):4088-91
references.pmid: 18573898
references.citation: PLoS One. 2010;5(4):e10107
references.pmid: 20404924
references.citation: Pathog Glob Health. 2013 Mar;107(2):78-87
references.pmid: 23683334
references.citation: Chirality. 2000 Jun;12(5-6):479-82
references.pmid: 10824174
references.citation: Clin Infect Dis. 2000 Oct;31(4):1104-7
references.pmid: 11049798
references.citation: World Health Organ Tech Rep Ser. 2010;(949):xii-xiii, 1-186, back cover
references.pmid: 21485694