| Autor: |
Amaral M; Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, 01246-000, Brazil., de Sousa FS; Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, São Paulo, 09972-270, Brazil., Silva TAC; Centre of Natural and Human Sciences, Federal University of ABC, Santo André, 09210-580, Brazil., Junior AJG; Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, 05403-000, Brazil., Taniwaki NN; Laboratory of Electron Microscopy, Instituto Adolfo Lutz, São Paulo, 01246-000, Brazil., Johns DM; Department of Biomedical Sciences, Oregon State University, Corvallis, Oregon, 97331, USA., Lago JHG; Centre of Natural and Human Sciences, Federal University of ABC, Santo André, 09210-580, Brazil., Anderson EA; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. edward.anderson@chem.ox.ac.uk., Tempone AG; Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, 01246-000, Brazil. andre.tempone@ial.sp.gov.br. |
| Abstrakt: |
Leishmaniasis is a neglected disease that affects more than 12 million people, with a limited therapy. Plant-derived natural products represent a useful source of anti-protozoan prototypes. In this work, four derivatives were prepared from neolignans isolated from the Brazilian plant Nectandra leucantha, and their effects against intracellular amastigotes of Leishmania (L.) infantum evaluated in vitro. IC 50 values between 6 and 35 µM were observed and in silico predictions suggested good oral bioavailability, no PAINS similarities, and ADMET risks typical of lipophilic compounds. The most selective (SI > 32) compound was chosen for lethal action and immunomodulatory studies. This compound caused a transient depolarization of the plasma membrane potential and induced an imbalance of intracellular Ca 2+ , possibly resulting in a mitochondrial impairment and leading to a strong depolarization of the membrane potential and decrease of ATP levels. The derivative also interfered with the cell cycle of Leishmania, inducing a programmed cell death-like mechanism and affecting DNA replication. Further immunomodulatory studies demonstrated that the compound eliminates amastigotes via an independent activation of the host cell, with decrease levels of IL-10, TNF and MCP-1. Additionally, this derivative caused no hemolytic effects in murine erythrocytes and could be considered promising for future lead studies. |
