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.

Searching for a potential antibacterial lead structure against bacterial biofilms among new naphthoquinone compounds

“…These results are in agreement to the in vitro low cytotoxicity profile recently described by our group to these compounds using the using mammalian cells (NCTC clone 929) in MTT colorimetric assay (Pinto et al . ; Fig. ).…”

“…This drug design plan led to a series of compounds with a satisfying solubility in aqueous biological media and yields up to 89% (Pinto et al . ), which implies the feasibility of using this synthetic route for producing these compounds in a large scale (Scheme ).…”

“…The arylsulfanylmethyl-[1,4]-naphthoquinones (5-40) were synthesized using a three-component process (Scheme 1), and the structures were confirmed by different methods, including 1 HNMR, IR and elemental analysis. The general procedure for preparing these compounds was previously described (Pinto et al 2014).…”

“…Recently, da Rocha et al developed a new threecomponent process for the C-alkylation of 1 with a simultaneous thiol addition that led to a series of new Calkyl-or C-arylsulfanylmethyl-[1,4]-naphthoquinones with moderate to good activity against the human malaria parasites Plasmodium falciparum (3D7) (Sharma et al 2013) and Leishmania (L.) infantum (Pinto et al 2014).…”

Synthesis of New Xanthenes Based on Lawsone and Coumarin via a Tandem Three‑Component Reaction

“…These latter compounds were screened against the human malaria parasite Plasmodium falciparum (3D7) 26 and Leishmania (L.) infantum and exhibited moderate to good activity. 27 The Synthesis of New Xanthenes Based on Lawsone and Coumarin via a Tandem Three-Component Reaction J. Braz. Chem.…”