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. 2014 Sep 22;19(9):15180-95.
doi: 10.3390/molecules190915180.

Synthesis, leishmanicidal activity and theoretical evaluations of a series of substituted bis-2-hydroxy-1,4-naphthoquinones

Morgana V de Araújo  1 , Patricia S O de Souza  2 , Aline C de Queiroz  3 , Carolina B B da Matta  4 , Anderson Brandão Leite  5 , Amanda Evelyn da Silva  6 , José A A de França  7 , Tania M S Silva  8 , Celso A Camara  9 , Magna S Alexandre-Moreira  10
Affiliations

Synthesis, leishmanicidal activity and theoretical evaluations of a series of substituted bis-2-hydroxy-1,4-naphthoquinones

Morgana V de Araújo et al. Molecules. .

Abstract

A series of eight substituted bis-2-hydroxy-1,4-naphthoquinone derivatives was synthesized through lawsone condensation with various aromatic and aliphatic aldehydes under mild acidic conditions. The title compounds were evaluated for antileishmanial activity in vitro against Leishmania amazonensis and Leishmania braziliensis promastigotes; six compounds showed good activity without significant toxic effects. The compound with the highest activity was used for an in vivo assay with Leishmania amazonensis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of compounds 1–3h.
Figure 1
Figure 1
In silico toxicity risk (tumorigenic, irritant and reproductive effects) for lawsone dimers. Theoretical toxicity risks calculated using the Osiris program. The toxicity profile scale for the side effects included low (1), medium (0.8) and high (0.6).
Figure 2
Figure 2
In silico comparison of the drug-like profile (drug-likeness (A) and drug score values (B)) for the bis-lawsone analogs and glucantime (GLT). These parameters were calculated using the Osiris program as described in the Experimental Section.
Figure 3
Figure 3
In vivo efficacy of 3a and glucantime treatments (30 μmol/kg/day × 28 days, i.p.) (A) in BALB/c mice infected wituh L. amazonensis. The lesion sizes were monitored weekly (non-infected control (B), infected control (C), glucantime (D) and 3a (E)). The values are the mean lesion sizes for five mice from each group, and the bars represent the standard error of the mean.
Figure 4
Figure 4
Parasite burden throughout the course of the 3a and glucantime treatments (30 μmol/kg/dia × 28 days, i.p.) in BALB/c mice infected with L. amazonensis. (A) Log10 of the parasites load in the infected ear; (B) Log10 of the parasites load in the draining lymph node. The infected ear and draining lymph node parasite loads were determined using a quantitative limiting-dilution assay. Values are the mean parasites load for five mice from each group, and the bars represent the standard error of the mean.
Figure 5
Figure 5
The in vivo effect from the 3a and glucantime treatments (30 μmol/kg/day × 28 days, i.p.) on the spleen weights of the BALB/c mice infected with L. amazonensis. The spleen weight was determined on last day of treatment. The values are the mean lesion size for five mice from each group, and the bars represent the standard error of the mean.
Figure 6
Figure 6
The in vivo effect from the 3a and glucantime treatments (30 μmol/k/day × 28 days, i.p.) on the serum ALT (A), AST (B), creatinine (C) and urea (D) levels in BALB/c mice infected with L. amazonensis. The lesion sizes were monitored weekly. The values are the mean lesion size for five mice from each group, and the bars represent the standard error of the mean.
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