title: Gibbilimbol analogues as antiparasitic agents--Synthesis and biological activity against Trypanosoma cruzi and Leishmania (L.) infantum.
abstract: The essential oils from leaves of Piper malacophyllum (Piperaceae) showed to be mainly composed by two alkenylphenol derivatives: gibbilimbols A and B. After isolation and structural characterization by NMR and MS data analysis, both compounds were evaluated against promastigote/amastigote forms of Leishmania (L.) infantum as well as trypomastigote/amastigote forms of Trypanosoma cruzi. The obtained results indicated that gibbilimbol B displayed potential against the tested parasites and low toxicity to mammalian cells, stimulating the preparation of several quite simple synthetic analogues in order to improve its activity and to explore the preliminary structure-activity relationships (SAR) data. Among the prepared derivatives, compound LINS03003 (n-octyl-4-hydroxybenzylamine) displayed the most potent IC50 values of 5.5 and 1.8 μM against amastigotes of T. cruzi and L. (L.) infantum, respectively, indicating higher activity than the natural prototype. In addition, this compound showed remarkable selectivity index (SI) towards the intracellular forms of Leishmania (SI=13.1) and T. cruzi (SI=4.3). Therefore, this work indicated that preparation of synthetic compounds structurally based in the bioactive natural products could be an interesting source of novel and selective compounds against these protozoan parasites.
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, Diadema, SP 09913-030, Brazil.
authors.forename: Marina T
authors.initials: MT
authors.lastname: Varela
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, Diadema, SP 09913-030, Brazil.
authors.forename: Roberto Z
authors.initials: RZ
authors.lastname: Dias
authors.affiliation: Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, Av. Dr. Arnaldo 355, São Paulo, SP 01246-902, Brazil.
authors.forename: Ligia F
authors.initials: LF
authors.lastname: Martins
authors.affiliation: Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, Av. Dr. Arnaldo 355, São Paulo, SP 01246-902, Brazil.
authors.forename: Daiane D
authors.initials: DD
authors.lastname: Ferreira
authors.affiliation: Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, Av. Dr. Arnaldo 355, São Paulo, SP 01246-902, Brazil.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Tempone
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, Diadema, SP 09913-030, Brazil.
authors.forename: Anderson K
authors.initials: AK
authors.lastname: Ueno
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, Diadema, SP 09913-030, Brazil. Electronic address: joao.lago@unifesp.br.
authors.forename: João Henrique G
authors.initials: JH
authors.lastname: Lago
authors.affiliation: Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, Diadema, SP 09913-030, Brazil. Electronic address: joao.fernandes@unifesp.br.
authors.forename: João Paulo S
authors.initials: JP
authors.lastname: Fernandes
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018314:Leishmania infantum / Q000187:drug effects; D009822:Oils, Volatile / Q000737:chemistry; D010636:Phenols / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D026321:Piperaceae / Q000737:chemistry / Q000378:metabolism; D018515:Plant Leaves / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D009822:Oils, Volatile; D010636:Phenols; C437729:gibbilimbol A; C437730:gibbilimbol B
keywords: Gibbilimbol A; Gibbilimbol B; Leishmanicidal; Natural product derivatives; SAR; Trypanocidal