Suzuki-Miyaura Coupling between 3-Iodolawsone and Arylboronic Acids. Synthesis of Lapachol Analogues with Antineoplastic and Antileishmanial Activities

Gomes, Sara L. S.; Militão, Gardênia Carmen Gadelha; Costa, Arinice M.; Pessoa, Cláudia; Costa-Lotufo, Letı́cia V.; Cunha-Júnior, Edézio Ferreira; Torres-Santos, Eduardo Caio; Costa, Paulo R.R.; Silva, Alcides J. M. da

doi:10.21577/0103-5053.20160326

Cited by 4 publications

(6 citation statements)

References 15 publications

(23 reference statements)

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“…This naphthoquinone presented dose-dependent activity in vitro , as on promastigotes (IC 50 = 116 ± 26 µM, 72h) as well intracellular amastigotes (IC 50 = 193 ± 19 μM, 48h) forms of L. ( V. ) braziliensis. These data corroborate with the previous report from our group, that has shown the in vitro effect of 3-PL against Leishmania ( L. ) amazonensis , in both promastigotes (IC 50 = 85 μM, 72h) and intracellular amastigotes (IC 50 = 25 μM, 72h) forms ( Gomes et al., 2017 ). The ability of 3-PL to have an effect against species of the different subgenus of the Leishmania (subgenus Leishmania and Viannia ), makes it even more promising.…”

Section: Discussionsupporting

confidence: 93%

“…The differences between the IC 50 values obtained in this study for L. (V.) braziliensis and those reported for L. (L.) amazonensis is expected due to the susceptibility variations between different subgenera and species of Leishmania , as well as the experimental conditions used. We established the IC 50 of 3-PL to L. ( V. ) braziliensis amastigotes at 48h, while IC 50 to L. ( L. ) amazonensis was made at 72h ( Gomes et al., 2017 ). The antileishmanial activity of lapachol, the naphthoquinone precursor molecule of 3-PL, presented wide values of IC 50 dependent on Leishmania strain and experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

“…The lapachol derivative 3-phenyl-lawsone, 3-PL, ( Figure 1A , insert) was synthesized in the Laboratory of Bioorganic Chemistry of the Federal University of Rio de Janeiro, Brazil by the Suzuki-Miyaura reaction as previously described ( Gomes et al., 2017 ). For assays, the 3-PL was dissolved in DMSO (Sigma Aldrich, St Louis, MO, USA) whose final concentration did not exceed 1%.…”

Section: Methodsmentioning

confidence: 99%

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Low doses of 3-phenyl-lawsone or meglumine antimoniate delivery by tattooing route are successful in reducing parasite load in cutaneous lesions of Leishmania (Viannia) braziliensis-infected hamsters

Meira

Gomes

Schaeffer

et al. 2023

Front. Cell. Infect. Microbiol.

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Current therapeutic ways adopted for the treatment of leishmaniasis are toxic and expensive including parasite resistance is a growing problem. Given this scenario, it is urgent to explore treatment alternatives for leishmaniasis. The aim of this study was to evaluate the effect of 3-phenyl-lawsone (3-PL) naphthoquinone on Leishmania (Viannia) braziliensis infection, both in vitro and in vivo, using two local routes of administration: subcutaneous (higher dose) and tattoo (lower dose). In vitro 3-PL showed low toxicity for macrophages (CC50 >3200 µM/48h) and activity against intracellular amastigotes (IC50 = 193 ± 19 µM/48h) and promastigotes (IC50 = 116 ± 26 µM/72h), in which induced increased ROS generation. Additionally, 3-PL up-regulated the production of cytokines such as tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), interleukin-6 (IL-6) and IL-10 in infected macrophages. However, the anti-amastigote action was independent of nitric oxide production. Treatment of hamsters infected with L. (V.) braziliensis from one week after infection with 3-PL by subcutaneous (25 µg/Kg) or tattooing (2.5 µg/Kg) route, during 3 weeks (3 times/week) or 2 weeks (2 times/week) significantly decreased the parasite load (p<0.001) in the lesion. The reduction of parasite load by 3-PL treatment was comparable to reference drug meglumine antimoniate administered by the same routes (subcutaneous 1mg/Kg and tattoo 0.1mg/Kg). In addition, treatment started from five weeks after infection with 3-PL per tattoo also decreased the parasite load. These results show the anti-leishmanial effect of 3-PL against L. (V.) braziliensis and its efficacy by subcutaneous (higher dose) and tattoo (lower dose) routes. In addition, this study shows that drug delivery by tattooing the lesion allows the use of lower doses than the conventional subcutaneous route, which may support the development of a new therapeutic strategy that can be adopted for leishmaniasis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Low doses of 3-phenyl-lawsone or meglumine antimoniate delivery by tattooing route are successful in reducing parasite load in cutaneous lesions of Leishmania (Viannia) braziliensis-infected hamsters

Meira

Gomes

Schaeffer

et al. 2023

Front. Cell. Infect. Microbiol.

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“…The present research was aimed at exploring, for the first time, the activity of lapachol against snake venoms. This prompted us to study the potential activity of the analogues based on the 2-hydroxi-naphthoquinone scaffold, which had been previously synthesized (Fig 1) [31], investigating their effects against some important activities of crude Bothrops atrox and Bothrops jararaca venoms under different experimental protocols in vivo and in vitro .…”

Section: Introductionmentioning

confidence: 99%

Lapachol and synthetic derivatives: in vitro and in vivo activities against Bothrops snake venoms

et al. 2019

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BackgroundIt is known that local tissue injuries incurred by snakebites are quickly instilled causing extensive, irreversible, tissue destruction that may include loss of limb function or even amputation. Such injuries are not completely neutralized by the available antivenins, which in general are focused on halting systemic effects. Therefore it is prudent to investigate the potential antiophidic effects of natural and synthetic compounds, perhaps combining them with serum therapy, to potentially attenuate or eliminate the adverse local and systemic effects of snake venom. This study assessed a group of quinones that are widely distributed in nature and constitute an important class of natural products that exhibit a range of biological activities. Of these quinones, lapachol is one of the most important compounds, having been first isolated in 1882 from the bark of Tabebuia avellanedae.Methodology/Principal findingsIt was investigated the ability of lapachol and some new potential active analogues based on the 2-hydroxi-naphthoquinone scaffold to antagonize important activities of Bothrops venoms (Bothrops atrox and Bothrops jararaca) under different experimental protocols in vitro and in vivo. The bioassays used to test the compounds were: procoagulant, phospholipase A2, collagenase and proteolytic activities in vitro, venom-induced hemorrhage, edematogenic, and myotoxic effects in mice. Proteolytic and collagenase activities of Bothrops atrox venom were shown to be inhibited by lapachol and its analogues 3a, 3b, 3c, 3e. The inhibition of these enzymatic activities might help to explain the effects of the analogue 3a in vivo, which decreased skin hemorrhage induced by Bothrops venom. Lapachol and the synthetic analogues 3a and 3b did not inhibit the myotoxic activity induced by Bothrops atrox venom. The negative protective effect of these compounds against the myotoxicity can be partially explained by their lack of ability to effectively inhibit phospholipase A2 venom activity. Bothrops atrox venom also induced edema, which was significantly reduced by the analogue 3a.ConclusionsThis research using a natural quinone and some related synthetic quinone compounds has shown that they exhibit antivenom activity; especially the compound 3a. The data from 3a showed a decrease in inflammatory venom effects, presumably those that are metalloproteinase-derived. Its ability to counteract such snake venom activities contributes to the search for improving the management of venomous snakebites.

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“…Some outstanding drug discovery programmes are widely used to find leading compounds, based on and inspired by the molecular modifications of natural products. Recent studies have demonstrated the potential of this approach for the discovery of new chemical entities in the treatment of neglected diseases (Carneiro et al., ; Cassamale et al., ; Costa et al., ; Dubar, Khalife, Brocard, Dive & Biot, ; Ferreira, ; Gomes et al., ; Jardim et al., ; Silva Júnior, Jardim, Menna‐Barreto & Castro, ; Varela et al., ; Zingales et al., ).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and antitrypanosomatid activities of 3,5‐diaryl‐isoxazole analogues based on neolignans veraguensin, grandisin and machilin G

et al. 2018

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Using bioisosterism as a medicinal chemistry tool, 16 3,5-diaryl-isoxazole analogues of the tetrahydrofuran neolignans veraguensin, grandisin and machilin G were synthesized via 1,3-dipolar cycloaddition reactions, with yields from 43% to 90%. Antitrypanosomatid activities were evaluated against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L. amazonensis and L. braziliensis. The most active compounds were 15, 16 and 19 with IC 50 values of 2.0, 3.3 and 9.5 μM against L. amazonensis and IC 50 values of 1.2, 2.1 and 6.4 μM on L. braziliensis, respectively. All compounds were noncytotoxic, showing lower cytotoxicity (>250 μM) than pentamidine (78.9 μM). Regarding the structure-activity relationship (SAR), the methylenedioxy group was essential to antileishmanial activity against promastigotes. Replacement of the tetrahydrofuran nucleus by an isoxazole core improved the antileishmanial activity. K E Y W O R D S bioisosterism, cycloaddition [3+2], isoxazole, neolignans 314 | TREFZGER ET al.

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Suzuki-Miyaura Coupling between 3-Iodolawsone and Arylboronic Acids. Synthesis of Lapachol Analogues with Antineoplastic and Antileishmanial Activities

Cited by 4 publications

References 15 publications

Low doses of 3-phenyl-lawsone or meglumine antimoniate delivery by tattooing route are successful in reducing parasite load in cutaneous lesions of Leishmania (Viannia) braziliensis-infected hamsters

Low doses of 3-phenyl-lawsone or meglumine antimoniate delivery by tattooing route are successful in reducing parasite load in cutaneous lesions of Leishmania (Viannia) braziliensis-infected hamsters

Lapachol and synthetic derivatives: in vitro and in vivo activities against Bothrops snake venoms

Design, synthesis and antitrypanosomatid activities of 3,5‐diaryl‐isoxazole analogues based on neolignans veraguensin, grandisin and machilin G

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