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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.)

Potential of 2-Hydroxy-3-Phenylsulfanylmethyl-[1,4]-Naphthoquinones against Leishmania (L.) infantum: Biological Activity and Structure-Activity Relationships

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Pinto, Erika G. [1, 2] ; Santos, Isabela O. [3] ; Schmidt, Thomas J. [4] ; Borborema, Samanta E. T. [2] ; Ferreira, Vitor F. [3] ; Rocha, David R. [3] ; Tempone, Andre G. [2]
Total Authors: 7
[1] Univ Sao Paulo, Inst Med Trop Sao Paulo, Sao Paulo - Brazil
[2] Adolfo Lutz Inst, Ctr Parasitol & Mycol, Sao Paulo - Brazil
[3] Univ Fed Fluminense, Inst Quim, Dept Quim Organ, Niteroi, RJ - Brazil
[4] Univ Munster, Inst Pharmaceut Biol & Phytochem, D-48149 Munster - Germany
Total Affiliations: 4
Document type: Journal article
Source: PLoS One; v. 9, n. 8 AUG 29 2014.
Web of Science Citations: 33

Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-{[}1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 mu M; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 mu M. The compounds containing the phenyl groups at R-1 and R-2 and with the fluorine substituent at the phenyl ring at R-2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-{[}1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis. (AU)

FAPESP's process: 11/23703-1 - Study of the therapeutic potential of drugs and synthetic compounds, free or loaded into NANOLIPOSOMES: an vitro and experimental approach
Grantee:Érika Gracielle Pinto
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 12/18756-1 - Evaluation of novel alternative therapies with synthetic drugs using in vitro and experimental models of Leishmania (L.) infantum chagasi
Grantee:André Gustavo Tempone Cardoso
Support type: Regular Research Grants