Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation

Chao, Maria Noelia; Storey, Melissa; Li, Catherine; Rodríguez, Maricel Gabriela; Salvo, Florencia Di; Szajnman, Sergio H.; Moreno, Silvia N.J.; Docampo, Roberto; Rodríguez, Juan B.

doi:10.1016/j.bmc.2017.10.016

Cited by 32 publications

(31 citation statements)

References 70 publications

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“…Similarly, increased selenium concentration in plasma has been proposed as a new defensive strategy against Leishmania infection (7). In recent years, our research group and others have been engaged in the design, synthesis, and biological evaluation of new selenium compounds with potent in vitro antitrypanosomatic activity (8), mainly against L. infantum. Our data revealed that some of these compounds possess potent activity with higher selectivity than the reference drugs miltefosine and edelfosine.…”

mentioning

confidence: 99%

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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confidence: 99%

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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“…The SQS was originally identified as chemotherapeutic target in T. cruzi by Urbina and coworkers by evaluating the in vitro and in vivo effects of SQS inhibitors [57][58][59][60]. New isosteric analogs based on 4-phenoxyphenoxyethyl thiocyanate, which was previously described as a good non-competitive allosteric inhibitor of T. cruzi SQS [57,61], were synthesized in order to understand the effect of different atoms on the activity of this inhibitor [62]. The analogues with the selenocyanate moiety were potent inhibitors of T. cruzi proliferation, and a selenocyanate derivative with a fluorophenoxy group was also a very effective inhibitor of T. cruzi growth with very low toxicity in vitro [62].…”

Section: Squalene Synthase (Sqs)mentioning

confidence: 99%

“…New isosteric analogs based on 4-phenoxyphenoxyethyl thiocyanate, which was previously described as a good non-competitive allosteric inhibitor of T. cruzi SQS [57,61], were synthesized in order to understand the effect of different atoms on the activity of this inhibitor [62]. The analogues with the selenocyanate moiety were potent inhibitors of T. cruzi proliferation, and a selenocyanate derivative with a fluorophenoxy group was also a very effective inhibitor of T. cruzi growth with very low toxicity in vitro [62]. In silico analysis showed that the presence of Se and not S increased the interaction between the compounds and SQS [62].…”

Section: Squalene Synthase (Sqs)mentioning

confidence: 99%

“…The analogues with the selenocyanate moiety were potent inhibitors of T. cruzi proliferation, and a selenocyanate derivative with a fluorophenoxy group was also a very effective inhibitor of T. cruzi growth with very low toxicity in vitro [62]. In silico analysis showed that the presence of Se and not S increased the interaction between the compounds and SQS [62]. The x-ray crystallographic structure of T. cruzi SQS was solved using coordinates of the human SQS [62].…”

Section: Squalene Synthase (Sqs)mentioning

confidence: 99%

“…In silico analysis showed that the presence of Se and not S increased the interaction between the compounds and SQS [62]. The x-ray crystallographic structure of T. cruzi SQS was solved using coordinates of the human SQS [62]. This enzyme catalyzes the first committed step in sterol biosynthesis leading to downstream synthesis of ergosterol.…”

Section: Squalene Synthase (Sqs)mentioning

confidence: 99%

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Advances in preclinical approaches to Chagas disease drug discovery

Villalta

Rachakonda

2019

Expert Opinion on Drug Discovery

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Introduction Chagas disease affects 8–10 million people worldwide, mainly in Latin America. The current therapy for Chagas disease is limited to nifurtimox and benznidazole, which are effective in treating only the acute phase of the disease but with severe side effects. Therefore, there is an unmet need for new drugs and for the exploration of innovative approaches which may lead to the discovery of new effective and safe drugs for its treatment. Areas covered The authors report and discuss recent approaches including structure-based design that have led to the discovery of new promising small molecule candidates for Chagas disease which affect prime targets that intervene in the sterol pathway of T. cruzi. Other trypanosome targets, phenotypic screening, the use of artificial intelligence and the challenges with Chagas disease drug discovery are also discussed. Expert opinion The application of recent scientific innovations to the field of Chagas disease have led to the discovery of new promising drug candidates for Chagas disease. Phenotypic screening brought new hits and opportunities for drug discovery. Artificial intelligence also has the potential to accelerate drug discovery in Chagas disease and further research into this is warranted.

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Organoselenium Compounds: Chemistry and Applications in Organic Synthesis

Sonego,

de Diego,

Szajnman

et al. 2023

Chemistry A European J

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Selenium, originally described as a toxin, turns out to be a crucial trace element for life that appears as selenocysteine and its dimer, selenocystine. From the point of view of drug developments, selenium‐containing drugs are isosteres of sulfur and oxygen with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. In this article, we have focused on the relevant features of the selenium atom, above all, the corresponding synthetic approaches to access a variety of organoselenium molecules along with the proposed reaction mechanisms. The preparation and biological properties of selenosugars, including selenoglycosides, selenonucleosides, selenopeptides, and other selenium‐containing compounds will be treated. We have attempted to condense the most important aspects and interesting examples of the chemistry of selenium into a single article.

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Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation

Cited by 32 publications

References 70 publications

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

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

Advances in preclinical approaches to Chagas disease drug discovery

Organoselenium Compounds: Chemistry and Applications in Organic Synthesis

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