2. Academic Validation
  3. Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi

Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi

  • Eur J Med Chem. 2019 Aug 15:176:162-174. doi: 10.1016/j.ejmech.2019.05.001.
Daiane D Ferreira 1,  Fernanda S Sousa 2,  Thais A Costa-Silva 3,  Juliana Q Reimão 4,  Ana C Torrecilhas 2,  Deidre M Johns 5,  Claire E Sear 6,  Kathia M Honorio 7,  João Henrique G Lago 3,  Edward A Anderson 8,  Andre G Tempone 9
Affiliations

Affiliations

  • 1 Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, 01246-000, Brazil.
  • 2 Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, Diadema, 09972-270, Brazil.
  • 3 Center of Natural and Human Sciences, Federal University of ABC, Santo André, 09210-580, Brazil.
  • 4 Faculdade de Medicina de Jundiaí, Rua Francisco Telles, 250 Vila Arens II 13202550, Jundiaí, SP, Brazil.
  • 5 Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR, 97331, USA.
  • 6 Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
  • 7 Escola de Artes, Ciências e Humanidades, Universidade de São Paulo, São Paulo, 03828-000, Brazil.
  • 8 Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. Electronic address: edward.anderson@chem.ox.ac.uk.
  • 9 Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, 01246-000, Brazil. Electronic address: andre.tempone@ial.sp.gov.br.
PMID: 31103897 DOI: 10.1016/j.ejmech.2019.05.001
Abstract

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 μM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 μM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 μM. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both Parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular Reactive Oxygen Species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies.

Keywords

Chagas disease; Drugs; Neolignans; Therapy; Trypanosoma cruzi.

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