Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Fernández-Rubio, Celia; Campbell, Daphne; Vacas, Andrés; Ibáñez, Elena; Moreno, Esther; Espuelas, Socorro; Calvo, Alfonso; Palop, Juan Antonio; Plano, Daniel; Sanmartín, Carmen; Nguewa, Paul A.

doi:10.1128/aac.00997-15

Cited by 30 publications

(26 citation statements)

References 38 publications

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“…In the last decade, anticancer drugs have been explored as candidates against infectious pathologies (9,20,21). Recently, several small molecules containing the Se atom have been reported as leishmanicidal agents (7). Here, we evaluated antileishmanial potential of some recently reported sulfur and selenium compounds bearing isothio-/isoselenocyanate and thio-/selenourea moieties attached to a naphthalimide or a phenylalkyl skeleton.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Karelia et al analyzed selenium derivatives of these naphthalimide analogs to discover the corresponding naphthalamideisoselenocyanate (NISC) and -selenourea (NSU) compounds, which led to the identification of dual topoisomerase 2 and the Akt pathway inhibitor activity of NISC-6 (16). In 2015, our group also demonstrated the leishmanicidal activity of selenocompounds (7), previously designed as antitumoral agents (17). In fact, selenium derivatives had been shown to reduce parasitemia and decrease clinical manifestations in infected mice (18).…”

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confidence: 97%

“…A strategy currently used to identify new leishmanicidal treatments is the so-called drug repurposing. Consequently, a large battery of antitumor compounds, such as gimatecan and other camptothecin derivatives, indenoisoquinolines, paclitaxel, and methylseleno-imidocarbamates, have demonstrated activity against Leishmania (3)(4)(5)(6)(7)(8)(9). However, the only oral drug reported to have an effect against this parasitic disease is miltefosine, an alkylphospholipid with antineoplastic effects and originally developed for breast cancer treatment.…”

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confidence: 99%

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Leishmanicidal Activity of Isoselenocyanate Derivatives

Fernández-Rubio

Larrea

Peña-Guerrero

et al. 2019

Antimicrob Agents Chemother

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Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania. In this study, the in vitro leishmanicidal activities of several organo-selenium and organo-sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, the isoselenocyanate derivative NISC-6, showed selectivity indexes 2- and 10-fold higher than those of the reference drug amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a trend similar to that observed previously for amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA, and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G1 phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis.

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Leishmanicidal Activity of Isoselenocyanate Derivatives

Fernández-Rubio

Larrea

Peña-Guerrero

et al. 2019

Antimicrob Agents Chemother

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“…After 96 h, benzyl isocyanate gave compound 7 as a yellow powder. Yield: 43%; mp 213 to 215°C; IR ʋ max ( , N===-(Diselanediyldibenzene-4,1-diyl)bis[1-(4-methoxybenzyl) , N===-(Diselanediyldibenzene-4,1-diyl)bis[1-(n-butyl) , N===-(Diselanediyldibenzene-4,1-diyl)bis[1-(n-hexyl) 13 General procedure for the synthesis of thioureas 12 to 22. To a solution of diselenide (1.17 mmol) in dioxane (25 ml), the corresponding isothiocyanate (2.34 mmol, 1:2 molar ratio) was added and the mixture was kept at room temperature from 48 h to 144 h. The solvent was removed under vacuum by rotatory evaporation and the residue was treated with ethyl ether (50 ml) and washed with water (100 ml).…”

Section: Methodsmentioning

confidence: 99%

“…Our data revealed that some of these compounds possess potent activity with higher selectivity than the reference drugs miltefosine and edelfosine. Additionally, leishmanicidal activity in infected macrophages (THP-1 cells) was comparable to that of edelfosine (9)(10)(11)(12)(13)(14)(15)(16). Among the different selenium entities tested, 4,4=-diaminodiphenyldiselenide showed one of the most promising leishmanicidal activities.…”

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confidence: 90%

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Díaz

Lucio

Moreno

et al. 2019

Antimicrob Agents Chemother

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A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC 50 ) values lower than that for the reference drug miltefosine (EC 50 , 2.84 M). In addition, the derivatives 9, 11, 42, and 47, with EC 50 between 1.1 and 1.95 M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC 50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.

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Selenium and protozoan parasitic infections: selenocompounds and selenoproteins potential

et al. 2022

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The current drug treatments against protozoan parasitic diseases including Chagas, malaria, leishmaniasis, and toxoplasmosis represent good examples of drug resistance mechanisms and have shown diverse side effects. Therefore, the identification of novel therapeutic strategies and drug compounds against such life-threatening diseases is urgent. According to the successful usage of selenium (Se) compounds-based therapy against some diseases, this therapeutic strategy has been recently further underlined against these parasitic diseases by targeting different parasite´s essential pathways. On the other hand, due to the important functions played by parasite selenoproteins in their biology (such as modulating the host immune response), they can be also considered as a novel therapeutic strategy by designing specific inhibitors against these important proteins. In addition, the immunomodulatory potentiality of these compounds to trigger T helper type 1 (Th1) cells and cytokinemediated immune response for the substantial induction of proinflammatory cytokines, thus, Se, selenoproteins, and parasite selenoproteins could be further investigated to find possible vaccine antigens. Herein, we collect and present the results of some studies regarding Se-based therapy against protozoan parasitic diseases and highlight relevant information and some viewpoints that might be insightful to advance toward more effective studies in the future.

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Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Cited by 30 publications

References 38 publications

Leishmanicidal Activity of Isoselenocyanate Derivatives

Leishmanicidal Activity of Isoselenocyanate Derivatives

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

Selenium and protozoan parasitic infections: selenocompounds and selenoproteins potential

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