title: Potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Leishmania (L.) infantum: biological activity and structure-activity relationships.
abstract: 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 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, 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.
authors.affiliation: Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, SP, Brazil; Instituto de Medicina Tropical de São Paulo, Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Erika G
authors.initials: EG
authors.lastname: Pinto
authors.affiliation: Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Niterói, RJ, Brazil.
authors.forename: Isabela O
authors.initials: IO
authors.lastname: Santos
authors.affiliation: Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, PharmaCampus, Münster, Germany.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schmidt
authors.affiliation: Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, SP, Brazil.
authors.forename: Samanta E T
authors.initials: SE
authors.lastname: Borborema
authors.affiliation: Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Niterói, RJ, Brazil.
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
authors.affiliation: Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Niterói, RJ, Brazil.
authors.forename: David R
authors.initials: DR
authors.lastname: Rocha
authors.affiliation: Centre for Parasitology and Mycology, Instituto Adolfo Lutz, São Paulo, SP, Brazil.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Tempone
mesh_terms: D000818:Animals; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D009285:Naphthoquinones; D014344:Trypanocidal Agents