Antitrypanosomal and antileishmanial activity of prenyl-1,2,3-triazoles

Porta, Exequiel O. J.; Jäger, Sebastián N.; Nocito, Isabel; Lepesheva, Galina I.; Serra, Esteban; Tekwani, Babu L.; Labadié, Guillermo R.

doi:10.1039/c7md00008a

Cited by 27 publications

(19 citation statements)

References 32 publications

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“…Reactions with aliphatic and benzylic azides produced a single product, with yields that are slightly better for the last ones. The reaction with the mixture of geranyl azides generated 3i , which was identified as an inseparable mixture of E and Z isomers ( 1 H NMR, 1.5:1), in accordance with our previous results (Porta et al, 2017a ). When farnesyl azide was used, a mixture of regioisomers was also obtained with the same ratio, but in this case they were separable ( Figure 3 ).…”

Section: Resultssupporting

confidence: 92%

“…Having prepared the pool of azides, we continued with the synthesis of a focused library of inhibitors through click chemistry. Reactions were conducted in a parallel solution synthesis setup under copper (II) sulfate catalytic conditions in water: t -BuOH (1:1), using sodium ascorbate as a reductant (Rostovtsev et al, 2002 ; Labadie et al, 2011 ; Porta et al, 2017a ). In general, reactions needed an excess of azides for completion and a reaction time was 18 h. All the products have 1,4-substitution on the 1,2,3,-triazol as expected, based on the original description of this methodology and our previous work (Porta et al, 2014 , 2017a ).…”

Section: Resultsmentioning

confidence: 99%

“…The Cu(I) azide-alkyne reaction, the quintessence of click chemistry, had a strong impact in many research areas including Medicinal Chemistry (Tron et al, 2008 ; Agalave et al, 2011 ). The easy reaction conditions has made this methodology very useful to rapidly prepare libraries of compounds, including antiparasitic drug candidates (Carvalho et al, 2010 ; Hamann et al, 2014 ; Porta et al, 2017a ).…”

Section: Discussionmentioning

confidence: 99%

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Targeting L-Proline Uptake as New Strategy for Anti-chagas Drug Development

et al. 2020

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L-Proline is an important amino acid for the pathogenic protists belonging to Trypanosoma and Leishmania genera. In Trypanosoma cruzi, the etiological agent of Chagas disease, this amino acid is involved in fundamental biological processes such as ATP production, differentiation of the insect and intracellular stages, the host cell infection and the resistance to a variety of stresses. In this study, we explore the L-Proline uptake as a chemotherapeutic target for T. cruzi. Novel inhibitors have been proposed containing the amino acid with a linker and a variable region able to block the transporter. A series of sixteen 1,2,3-triazolyl-proline derivatives have been prepared for in vitro screening against T. cruzi epimastigotes and proline uptake assays. We successfully obtained inhibitors that interfere with the amino acid internalization, which validated our design targeting the metabolite's transport. The presented structures are one of few examples of amino acid transporter inhibitors. The unprecedent application of this strategy on the development of new chemotherapy against Chagas disease, opens a new horizon on antiparasitic drug development against parasitic diseases and other pathologies.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Targeting L-Proline Uptake as New Strategy for Anti-chagas Drug Development

et al. 2020

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“…[16] The triazoles were synthesized by reaction of S-propargyl thiosalicylate 1 with the azide under conventional conditions using copper sulphate, sodium ascorbate in t BuOH:H2O (1:1). [17] The collection of sixteen new products was obtained with an average yield of 81% after purification. Scheme 3.…”

Section: Methodsmentioning

confidence: 99%

Repositioning Salirasib as a new antimalarial agent

et al. 2019

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“…Reactions were conducted in a parallel solution synthesis setup under copper (II) sulphate catalytic conditions in water:t-BuOH (1:1), using sodium ascorbate as a reductant. [49][50][51] In general, reactions needed an excess of azides for completion and a reaction time was 18 h. All the products have 1,4-substitution on the 1,2,3,-triazol as expected, based on the original description of this methodology and our previous work. [40,50] Reactions with aliphatic and benzylic azides produced a single product, with yields that are slightly better for the last ones.…”

Section: Synthesismentioning

confidence: 80%

New L-proline uptake inhibitors with anti-Trypanosoma cruzi activity

Fargnoli¹,

Panozzo-Zénere²,

Pagura³

et al. 2019

Preprint

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L-Proline is an important amino acid for the pathogenic protists belonging to Trypanosoma and Leishmania genera. In Trypanosoma cruzi, the etiological agent of Chagas disease, this amino acid is involved in fundamental biological processes such as ATP production, differentiation of the insect and intracellular stages, the host cell infection and the resistance to a variety of stresses, including nutritional and osmotic as well as oxidative imbalance. In this study, we explore the L-Proline uptake as a chemotherapeutic target for T. cruzi. For this, we propose a novel rational to design inhibitors containing this amino acid as a recognizable motif. This rational consists of conjugating the amino acid (proline in this case) to a linker and a variable region able to block the transporter. We obtained a series of sixteen 1,2,3-triazolyl-proline derivatives through alkylation and copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry) for in vitro screening against T. cruzi epimastigotes, trypanocidal activity and proline uptake. We successfully obtained inhibitors that are able to interfere with the amino acid uptake, which validated the first example of a rationally designed chemotherapeutic agent targeting a metabolite's transport. Additionally, we designed and prepared fluorescent analogues of the inhibitors that were successfully taken up by T. cruzi, allowing following up their intracellular fate. In conclusion, we successfully designed and produced a series of metabolite uptake inhibitors. This is one of few examples of rationally designed amino acid transporter inhibitor, being the first case where the strategy is applied on the development of chemotherapy against Chagas disease. This unprecedented development is remarkable having in mind that only a small percent of the metabolite transporters has been studied at the structural and/or molecular level.

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Antitrypanosomal and antileishmanial activity of prenyl-1,2,3-triazoles

Cited by 27 publications

References 32 publications

Targeting L-Proline Uptake as New Strategy for Anti-chagas Drug Development

Targeting L-Proline Uptake as New Strategy for Anti-chagas Drug Development

Repositioning Salirasib as a new antimalarial agent

New L-proline uptake inhibitors with anti-Trypanosoma cruzi activity

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