Selenocyanates and diselenides: A new class of potent antileishmanial agents

Self Cite

fThe generation of new antileishmanial drugs has become a priority. Selenium and its derivatives stand out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations, and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug similarity parameters, we observed that two of them, called compounds 2b [methyl-N,N=-di(thien-2-ylcarbonyl)-imidoselenocarbamate] and 4b [methyl-N,N=-di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate], exhibit low 50% inhibitory concentrations (IC 50 s) (<3 M) and good selectivity indexes (SIs) (>5) in Leishmania major promastigotes and lack toxicity on macrophages. In addition, in analysis of their therapeutic potential against L. major in vitro infection, both compounds display a dramatic reduction of amastigote burden (ϳ80%) with sublethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for defense against intracellular pathogens. Compounds 2b and 4b were demonstrated to cause cell cycle arrest in G 1 . Interestingly, evaluation of expression of genes related to proliferation (PCNA), treatment resistance (ABC transporter and alpha-tubulin), and virulence (quinonoid dihydropteridine reductase [QDPR]) showed several alterations in gene expression profiling. All these results prompt us to propose both compounds as candidates to treat leishmanial infections.

Section: Discussionmentioning

confidence: 99%

Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates

Fernández-Rubio

Campbell

Vacas

et al. 2015

Self Cite

“…The group I compounds were obtained by the nucleophilic substitution of the halogen atom of the corresponding alkyl or benzyl halides by a selenocyanate group using potassium selenocyanate (KSeCN) under reflux conditions according to previously reported methods (29,30). Thus, the corresponding organic halide was refluxed for 2 to 4 h in acetone with potassium selenocyanate.…”

Section: Methodsmentioning

confidence: 99%

“…The solid obtained was purified either by recrystallization or by washing with different solvents. Group II derivatives were synthesized by reduction of the corresponding selenocyanate from group I using sodium borohydride following the previously described procedure (29,30). In order to do so, sodium borohydride was added with caution to a stirring solution of the corresponding selenocyanate from group I in absolute ethanol.…”

Section: Novel Agents Against Leishmania Speciesmentioning

confidence: 99%

“…The results obtained for the reference drug, meglumine antimonate, were included in all cases for comparison. Biological data evidenced that half of the screened compounds (compounds 8,9,10,11,13,15,17,18,20,21,24,26,29,33,35,37,38,42,43,44,45,46, 47, and 48) showed high levels of bioactivity against L. infantum, presenting greater potency than the reference drug, meglumine antimonate, against both forms (IC 50 s, 18.0 M for promastigotes and 24.2 M for amastigotes).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Library of Seleno-Compounds as Novel Agents against Leishmania Species

Martín‐Montes

Plano

Martín‐Escolano

et al. 2017

Self Cite

The in vitro leishmanicidal activities of a series of 48 recently synthesized selenium derivatives against Leishmania infantum and Leishmania braziliensis parasites were tested using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds for J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (compounds 8, 10, 11, 15, 45, and 48) showed selectivity indexes higher than those of the reference drug, meglumine antimonate (Glucantime), for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, data on infection rates and amastigote numbers per macrophage showed that compounds 8, 10, 11, 15, 45, and 48 were the most active against both Leishmania species studied. The observed changes in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe superoxide dismutase (Fe-SOD) in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials, and straightforward synthesis make these compounds appropriate molecules for the development of affordable antileishmanicidal agents.KEYWORDS Leishmania, selenium, superoxide dismutase, glucose metabolism L eishmaniasis, caused by the intracellular protozoan Leishmania, is transmitted by the bite of phlebotomine sand flies and is endemic in 98 countries, with over 350 million people being at risk (1). Environmental, demographic, and human behavioral factors and coinfections contribute to the changing epidemiology of the disease and to its recent worldwide spread. Clinical manifestations are divided into visceral leishmaniasis (VL; or kala-azar) (2) and the forms cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (ML). CL remains the most common form of leishmaniasis both in general and in international travelers (3-5).The drugs available for the treatment of VL and severe CL include pentavalent antimonials (SbV), deoxycholate, amphotericin B (AMB), and miltefosine (MIL), all of which have high levels of toxicity and/or require long-duration treatment schedules (5, 6). Moreover, with the exception of MIL, all these drugs must be administered by the parenteral route (7).In the last decade, resistance to SbV has increased mainly due to low rates of compliance with the treatment schedule. In areas where the parasites are resistant to

“…On the other hand, the incorporation of selenium into novel nanomaterials has demonstrated effectiveness in the treatment of leishmaniasis (20). We have reported (21)(22)(23)(24) new selenium compounds with potent in vitro antiparasitic activity against Leishmania infantum and Leishmania major, and selectivity indexes higher than those observed for the reference drugs miltefosine, edelfosine, and paromomycin. Additionally, some of them induced nitric oxide production and alterations in gene expression profiling related to proliferation (PCNA), treatment resistance (ABC-transporter and ␣-tubulin), and virulence (QDPR) (23).…”

mentioning

confidence: 99%

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Baquedano

Alcolea

Toro

et al. 2016

Self Cite

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED 50 ) values ranging from 0.45 to 1.27 M and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3=-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.