Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: Synthesis and antileishmanial effects against Leishmania amazonensis

Melos, Jorge Luiz R. de; Torres-Santos, Eduardo Caio; Faiões, Viviane dos Santos; Cistia, Catarina de Nigris Del; Sant’Anna, Carlos Maurício R.; Rodrigues-Santos, Cláudio Eduardo; Echevarrı́a, Aurea

doi:10.1016/j.ejmech.2015.09.009

Cited by 35 publications

(19 citation statements)

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“…Another modification that improved the activity was the addition of the methylenedioxy group ( 2d ). This group has demonstrated the ability to potentiate the activity of triazole compounds [ 32 ], analogs of camptothecin [ 33 ], thiosemicarbazones [ 34 ] and secondary metabolites isolated from the stem bark of Rollinia emarginata [ 35 ]. We verified this potential in the phenotypic trials on L. amazonensis and L. braziliensis ; however, this effect was not seen in promastigotes of L.infantum .…”

Section: Discussionmentioning

confidence: 99%

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Faiões

Frota

Cunha-Júnior

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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BackgroundDespite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones.MethodsThe second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells.ResultsIn this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production.ConclusionsThe data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.

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Section: Discussionmentioning

confidence: 99%

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Faiões

Frota

Cunha-Júnior

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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“…[17,18] However,IC 50 values achieved by our tested compounds were on the same order as those described for two other reference drugs against promastigotes of L. amazonensis. In fact, for miltefosine, IC 50 values of 16.8 mm [45] and 3.4 mm [46] have been published, whereas for pentamidine, values of 29.9 mm (10.19 mgmL À1 ) [47] and 4.8 mm [48] have been recorded.…”

Section: In Vitro Activity Against L Amazonensis Promastigotesmentioning

confidence: 99%

Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2‐Benzyl‐5‐nitroindazole‐Derived Amines

et al. 2018

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Three different series of new 5-nitroindazole derivatives-1-(ω-aminoalkyl)-2-benzylindazolin-3-ones (series A; ten compounds), 3-(ω-aminoalkoxy)-2-benzylindazoles (series B; four compounds) and 3-alkylamino-2-benzylindazoles (series C; five compounds)-have been synthesized and evaluated against the protozoan parasites Trypanosoma cruzi, Leishmania amazonensis, and Trichomonas vaginalis: etiological agents of Chagas disease, cutaneous leishmaniasis, and trichomoniasis, respectively. Many indazoles of series A, B, and C were efficient against T. cruzi. Some compounds in series A, after successfully passing the preliminary screening for epimastigotes, exhibited activity values against amastigotes of several T. cruzi strains that were better than or similar to those shown by the reference drug benznidazole and displayed low nonspecific toxicity against mammalian cells. On the other hand, preliminary studies against promastigotes of L. amazonensis showed high leishmanicidal activity for some derivatives of series A and C. With regard to activity against T. vaginalis, some indazoles of series B and C were rather efficient against trophozoites of a metronidazole-sensitive isolate and showed low nonspecific toxicities toward Vero cell cultures. Additionally, some of these compounds displayed similar activity against metronidazole-sensitive and resistant isolates, showing the absence of cross-resistance between these derivatives and the reference drug.

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“…It can be found in some essential oils, vanilla and camphor,25, 26, 27 and has been shown to have antibacterial28 and anxiolytic effects 29. Moreover, some piperonal derivatives show a potential anticancer effect,30,31 antileishmanial activity,32 and other pharmacological effects 33…”

Section: Introductionmentioning

confidence: 99%

Selective Enzymatic Transformation to Aldehydes in vivo by Fungal Carboxylate Reductase from Neurospora crassa

et al. 2016

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The enzymatic reduction of carboxylic acids is in its infancy with only a handful of biocatalysts available to this end. We have increased the spectrum of carboxylate‐reducing enzymes (CARs) with the sequence of a fungal CAR from Neurospora crassa OR74A (NcCAR). NcCAR was efficiently expressed in E. coli using an autoinduction protocol at low temperature. It was purified and characterized in vitro, revealing a broad substrate acceptance, a pH optimum at pH 5.5–6.0, a T m of 45 °C and inhibition by the co‐product pyrophosphate which can be alleviated by the addition of pyrophosphatase. The synthetic utility of NcCAR was demonstrated in a whole‐cell biotransformation using the Escherichia coli K‐12 MG1655 RARE strain in order to suppress overreduction to undesired alcohol. The fragrance compound piperonal was prepared from piperonylic acid (30 mM) on gram scale in 92 % isolated yield in >98% purity. This corresponds to a productivity of 1.5 g/L/h.

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Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: Synthesis and antileishmanial effects against Leishmania amazonensis

Cited by 35 publications

References 40 publications

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2‐Benzyl‐5‐nitroindazole‐Derived Amines

Selective Enzymatic Transformation to Aldehydes in vivo by Fungal Carboxylate Reductase from Neurospora crassa

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