title: New alkenyl derivative from Piper malacophyllum and analogues: Antiparasitic activity against Trypanosoma cruzi and Leishmania infantum.
abstract: Alkylphenols isolated from Piper malacophyllum (Piperaceae), gibbilimbols A and B, showed interesting activity against the parasites Trypanosoma cruzi and Leishmania infantum. In continuation to our previous work, a new natural product from the essential oil of the leaves of P. malacophyllum was isolated, the 5-[(3E)-oct-3-en-1-il]-1,3-benzodioxole, and also a new set of five compounds was prepared. The antiparasitic activity of the natural product was evaluated in vitro against these parasites, indicating potential against the promastigote/trypomastigote/amastigote forms (IC5032-83 μm) of the parasites and low toxicity (CC50> 200 μm) to mammalian cells. The results obtained to the synthetic compounds indicated that the new derivatives maintained the promising antiparasitic activity, but the cytotoxicity was considerably lowered. The amine derivative LINS03011 displayed the most potent IC50values (13.3 and 16.7 μm) against amastigotes of T. cruzi and L. infantum, respectively, indicating comparable activity to the phenolic prototype LINS03003, with threefold decreased (CC5073.5 μm) cytotoxicity, leading the selectivity index (SI) towards the parasites up to 24.5. In counterpart, LINS03011 has not shown membrane disruptor activity in SYTOX Green model. In summary, this new set showed the hydroxyl is not essential for the antiparasitic activity, and its substitution could decrease the toxicity to mammalian cells.
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
authors.forename: Marina T
authors.initials: MT
authors.lastname: Varela
authors.affiliation: Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, São Paulo, SP, Brazil.|Instituto de Medicina Tropical de São Paulo, Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Marta L
authors.initials: ML
authors.lastname: Lima
authors.affiliation: Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, São Paulo, SP, Brazil.
authors.forename: Mariana K
authors.initials: MK
authors.lastname: Galuppo
authors.affiliation: Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, São Paulo, SP, Brazil.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Tempone
authors.affiliation: Instituto de Química, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil.
authors.forename: Alberto
authors.initials: A
authors.lastname: de Oliveira
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: João Henrique G
authors.initials: JHG
authors.lastname: Lago
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
authors.forename: João Paulo S
authors.identifier: http://orcid.org/0000-0002-9089-273X
authors.initials: JPS
authors.lastname: Fernandes
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy; D004149:Dioxoles / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D009822:Oils, Volatile / Q000737:chemistry; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D031701:Piper / Q000737:chemistry*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D004149:Dioxoles; D009822:Oils, Volatile; D010636:Phenols; D014344:Trypanocidal Agents; C437729:gibbilimbol A; C040539:1,3-benzodioxole
keywords: SAR; gibbilimbol analogues; leishmanicidal; natural product derivatives; trypanocidal