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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

A semi-synthetic neolignan derivative from dihydrodieugenol B selectively affects the bioenergetic system of Leishmania infantum and inhibits cell division

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Amaral, Maiara [1] ; de Sousa, Fernanda S. [2] ; Silva, Thais A. Costa [3] ; Junior, Andres Jimenez G. [4] ; Taniwaki, Noemi N. [5] ; Johns, Deid Re M. [6] ; Lago, Joao Henrique G. [3] ; Anderson, Edward A. [7] ; Tempone, Andre G. [1]
Total Authors: 9
[1] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246000 Sao Paulo - Brazil
[2] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09972270 Sao Paulo - Brazil
[3] Fed Univ ABC, Ctr Nat & Human Sci, BR-09210580 Santo Andre - Brazil
[4] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, BR-05403000 Sao Paulo - Brazil
[5] Adolfo Lutz Inst, Lab Electron Microscopy, BR-01246000 Sao Paulo - Brazil
[6] Oregon State Univ, Dept Biomed Sci, Corvallis, OR 97331 - USA
[7] Univ Oxford, Chem Res Lab, 12 Mansfield Rd, Oxford OX1 3TA - England
Total Affiliations: 7
Document type: Journal article
Source: SCIENTIFIC REPORTS; v. 9, APR 16 2019.
Web of Science Citations: 3

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. IC50 values between 6 and 35 mu M 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 Ca2+, 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. (AU)

FAPESP's process: 18/10279-6 - Selection and Optimization of New Drug Candidates for Leishmaniasis and Chagas Disease
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants
FAPESP's process: 15/50075-2 - Brazilian biodiversity as a source for novel drug scaffolds against neglected protozoan diseases
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants
FAPESP's process: 18/07885-1 - Biomolecules from plant species of remnant areas of the Atlantic Forest and Cerrado to treat neglected tropical diseases - chemical and pharmacological aspects
Grantee:João Henrique Ghilardi Lago
Support type: BIOTA-FAPESP Program - Regular Research Grants