Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities

Lévaique, Hélène; Pamlard, Olivier; Apel, Cécile; Bignon, Jérôme; Arriola, Margaux; Kuhner, Robin; Awang, Khalijah; Loiseau, Philippe M.; Litaudon, Marc; Pomel, Sébastien

doi:10.3390/molecules26061551

Cited by 5 publications

(6 citation statements)

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“…This compound is effective against the L. infantum parasite but only when the parasite is in the macrophage. This type of host-directed mechanism of action has been previously described in the literature [23][24][25][26][27]. We thus studied pharmacomodulations on the quinolone scaffold by varying the substituents on the amide function of zanthosimuline 7 and on the tetracyclic product 11.…”

Section: Resultsmentioning

confidence: 76%

“…Cytotoxicity was evaluated on RAW 264.7 macrophages [26]. Cells were plated in 96-well microplates at a density of 2 × 10 4 cells per well.…”

Section: In Vitro Cytotoxicity Evaluation Of Compoundsmentioning

confidence: 99%

“…Concerning the evaluation on intramacrophage amastigotes, the determination of the cytotoxicity as presented above was necessary to use the highest drug concentrations to be studied on the intramacrophage amastigote model. The evaluation on the intracellular form on the parasite was performed as previously described [26]. RAW264.7 macrophages were plated in 16-well Lab-Tek chamber slides (Thermo-Fisher Villebon-sur-Yvette, France) at a density of 2 × 10 4 cells per well and incubated for 24 h at 37 • C with 5% CO 2 .…”

Section: In Vitro Antileishmanial Evaluation Of Compounds On Axenic A...mentioning

confidence: 99%

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Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

et al. 2022

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Quinoline derivatives and especially quinolones are considered as privileged structures in medicinal chemistry and are often associated with various biological properties. We recently isolated a series of original monoterpenyl quinolones from the bark of Codiaeum peltatum. As this extract was found to have a significant inhibitory activity against a Leishmania species, we decided to study the anti-leishmanial potential of this type of compound. Leishmaniasis is a serious health problem affecting more than 12 million people in the world. Available drugs cause harmful side effects and resistance for some of them. With the aim of finding anti-leishmanial compounds, we developed a synthetic strategy to access natural quinolones and analogues derived from zanthosimuline. We showed the versatility of this natural compound toward cyclization conditions, leading to various polycyclic quinolone-derived structures. The natural and synthetic compounds were evaluated against amastigote forms of Leishmania infantum. The results obtained confirmed the interest of this family of natural compounds but also revealed promising activities for some intermediates deriving from zanthosimuline. Following the same synthetic strategy, we then prepared 14 new analogues. In this work, we identified two promising molecules with good activities against intramacrophage L. infantum amastigotes without any cytotoxicity. We also showed that slight changes in amide functional groups affect drastically their anti-parasitic activity.

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Section: Resultsmentioning

confidence: 76%

“…Cytotoxicity was evaluated on RAW 264.7 macrophages [26]. Cells were plated in 96-well microplates at a density of 2 × 10 4 cells per well.…”

Section: In Vitro Cytotoxicity Evaluation Of Compoundsmentioning

confidence: 99%

Section: In Vitro Antileishmanial Evaluation Of Compounds On Axenic A...mentioning

confidence: 99%

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Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

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“…Moreover, these mutant parasites are rapidly cleared in infected mice, showing that GDP-MP is essential for amastigote survival both in vitro and in vivo [9,10]. Moreover, several differences have been identified in the catalytic site of leishmanial GDP-MP in comparison with the human counterpart [11,12], making this enzyme an attractive therapeutic target to develop new specific antileishmanial agents [13]. Furthermore, some studies highlight a possible relationship between GDP-MP and drug resistance [14,15].…”

Section: Introductionmentioning

confidence: 99%

Minor Impact of A258D Mutation on Biochemical and Enzymatic Properties of Leishmania infantum GDP-Mannose Pyrophosphorylase

et al. 2022

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Background: Leishmaniasis, a vector-borne disease caused by the protozoan parasite from the genus Leishmania, is endemic to tropical and subtropical areas. Few treatments are available against leishmaniasis, with all presenting issues of toxicity, resistance, and/or cost. In this context, the development of new antileishmanial drugs is urgently needed. GDP-mannose pyrophosphorylase (GDP-MP), an enzyme involved in the mannosylation pathway, has been described to constitute an attractive therapeutic target for the development of specific antileishmanial agents. Methods: In this work, we produced, purified, and analyzed the enzymatic properties of the recombinant L. infantum GDP-MP (LiGDP-MP), a single leishmanial GDP-MP that presents mutation of an aspartate instead of an alanine at position 258, which is also the single residue difference with the homolog in L. donovani: LdGDP-MP. Results: The purified LiGDP-MP displayed high substrate and cofactor specificities, a sequential random mechanism of reaction, and the following kinetic constants: Vm at 0.6 µM·min−1, Km from 15–18 µM, kcat from 12.5–13 min−1, and kcat/Km at around 0.8 min−1µM−1. Conclusions: These results show that LiGDP-MP has similar biochemical and enzymatic properties to LdGDP-MP. Further studies are needed to determine the advantage for L. infantum of the A258D residue change in GDP-MP.

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“…As the second deadliest tropical disease and the fourth most morbid, leishmaniasis is present in 88 countries [1] . There are two million new cases each year and 12 million people are currently infected [15] . The most serious visceral leishmaniasis (VL) is responsible for around 50,000 deaths each year, with new cases estimated at around 500,000 per year.…”

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confidence: 99%

1,2,3-triazenes and 1,2,3-triazoles as antileishmanial, antitrypanosomal, and antiplasmodial agents

et al. 2022

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Trypanosomiasis, leishmaniasis and malaria are tropical diseases that affect poor populations and the classical drugs are toxic and select drug resistance. There is, therefore, an urgent need to find effective therapeutic agents accessible to developing countries that bear the brunt of morbidity and mortality.In this study, we evaluated the in vitro activities of fourteen 1,2,3-triazenes and 1,2,3triazoles against Trypanosoma brucei gambiense, Leishmania donovani and Plasmodium falciparum. Moreover, the synthesis of two new products among them will be described.The 1,4-disubstituted 1,2,3-triazenes showed better activities than 1,2,3-triazoles against Leishmania donovani with selectivity indexes greater than 100. Thus, compound 2b was the most effective one against axenic amastigote forms of Leishmania donovani LV9 with an IC 50 of 0.89 ± 0.41 M, and against the intramacrophagic amastigote forms, with an IC 50 value at 0.99 ± 0.36 M.Compounds 3a, a 1,2,3-triazene and 8, a triazole analogue of the cholesterol side chain, showed the best trypanocidal activities against Trypanosoma brucei gambiense with IC 50 of 3.45 ± 0.09 M and 3.99 ± 0.23 M, respectively.The most interesting result against the Plasmodium falciparum 3D7 strain was obtained with 5b with an IC 50 value of 1.29 ± 0.15 M.The present study revealed that 1,2,3-triazenes and 1,4-disubstituted 1,2,3-triazoles are chemical entities exhibiting an antiparasite potential that could lead to a new class of drug candidates.

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Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities

Cited by 5 publications

References 29 publications

Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

Minor Impact of A258D Mutation on Biochemical and Enzymatic Properties of Leishmania infantum GDP-Mannose Pyrophosphorylase

1,2,3-triazenes and 1,2,3-triazoles as antileishmanial, antitrypanosomal, and antiplasmodial agents

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