Inhibitors of
            <i>Leishmania</i>
            GDP-Mannose Pyrophosphorylase Identified by High-Throughput Screening of Small-Molecule Chemical Library

Lackovic, Kurt; Parisot, John P; Sleebs, Nerida; Baell, Jonathan B.; Debien, Laurent; Watson, Keith G.; Curtis, Joan M.; Handman, Emanuela; Street, Ian P.; Kędzierski, Łukasz

doi:10.1128/aac.01634-09

Cited by 39 publications

(31 citation statements)

References 29 publications

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“…Recent work has confirmed the interesting antileishmanial properties of other quinoline series (2,6,18). In addition, quinolines have recently been found to inhibit leishmanial GDP-mannose-pyrophosphorylase, an enzyme system producing a range of mannose-rich glycoconjugates that are essential for parasite survival and virulence (7). This potential for selective action against a Leishmania-specific target makes quinolines a promising series of antileishmanial drugs.…”

mentioning

confidence: 76%

In Vitro Activities of New 2-Substituted Quinolines against Leishmania donovani

Loiseau

Gupta

Verma

et al. 2011

Antimicrob Agents Chemother

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A series of 9 quinolines and 18 styrylquinolines was evaluated for the drugs' in vitro antileishmanial activities and cytotoxicities. The 7-aroylstyrylquinoline scaffold appeared to be the most promising one, with the most interesting compound, no. 35, exhibiting a 50% inhibitory concentration (IC 50 ) of 1.2 M and a selectivity index value of 121.5. Compound 35 was 10-fold and 8-fold more active than miltefosine and sitamaquine, the reference compounds, with selectivity indexes 607-fold and 60-fold higher, respectively.Leishmaniasis is a family of parasitic diseases that affect about 12 million people in tropical and subtropical areas in the form of three clinical expressions: visceral leishmaniasis, which is fatal in the absence of treatment; muco-cutaneous leishmaniasis; and cutaneous leishmaniasis, which is often selfcuring. Classical drugs such as antimonials (Pentostam and Glucantime) are toxic, and drug resistance is increasing dangerously in the field (3). A liposomal amphotericin B formulation (AmBisome) less toxic than amphotericin B deoxycholate is gradually becoming the first-line therapy, especially in immunocompromised patients, but this drug must be administered by a parenteral route (11). Miltefosine (Impavido) was the first drug registered against visceral leishmaniasis in the last decade; however, its toxicity and the appearance of drug resistance justify the search for new chemical series in order to find an orally safe and active drug (8).Quinolines substituted at the 2-position have shown in vivo activities against Leishmania donovani, and many compounds have been synthesized over the last decade (14). The Drug for Neglected Diseases Initiative (DNDi) has been considering this series for evaluation in preclinical development for about a year and a half. However, although promising, the series still requires improvements, and here we report the in vitro antileishmanial evaluation of new quinoline derivatives, including 2-[2-aryl(ethenyl)]-substituted quinoline (2-styrylquinolines) bearing additional aroyl/acyl groups at the C-7 position. In addition, some compounds within this series were recently shown to display substantial antiviral activity in HIV-infected cells (13,22).The synthesis of most of the compounds has been previously reported. Briefly, Kolbe carbonation of 8-hydroxyquinaldine afforded the pivotal hydroxyacid compound 1 (9), which was further elaborated into the 5-iodoquinaldine compound 12 and amide compound 17 (13). Similarly, bromination of the C-5 position and protection of the salicylic moiety provided 5-bromoquinaldine compound 2, which was engaged in a modified Suzuki cross-coupling reaction to give 5-arylated derivatives 14 to 16 (19). Styrylquinoline compounds 19 to 27 were prepared from the corresponding quinaldine compound 3 by Perkin-type condensation in refluxing acetic anhydride, followed by hydrolysis in a pyridine-water mixture (10,16,21,22). Finally, the 7-aroyl-stryryquinoline derivatives 28 to 35 were obtained via the 7-bromostyrylquinoline compound 5 accordin...

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confidence: 76%

In Vitro Activities of New 2-Substituted Quinolines against Leishmania donovani

Loiseau

Gupta

Verma

et al. 2011

Antimicrob Agents Chemother

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“…Compound 100 , a 4-substituted quinoline with a chloride in position 7, has been previously described to be the most potent L. major GDP-MP inhibitor identified by high throughput screening with an IC 50 at 0.58 µM 8 . This compound presents an IC 50 on L. donovani and L. mexicana intramacrophage amastigotes between 20 and 30 µM, which is consistent with the IC 50 previously reported at 21.9 µM in L. major 8 . Nonetheless, compound 100 exhibits only moderate or no inhibition on the leishmanial enzymes Ld GDP-MP and Lm GDP-MP, respectively, while h GDP-MP is inhibited with a noticeable K i at around 20 µM.…”

Section: Discussionmentioning

confidence: 99%

Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads

Mao¹,

Daligaux²,

Lazar³

et al. 2017

Sci Rep

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Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmanial target is an attractive strategy to expand the chemotherapeutic arsenal. GDP-Mannose Pyrophosphorylase (GDP-MP) is a prominent therapeutic target involved in host-parasite recognition which has been described to be essential for parasite survival. In this work, we produced and purified GDP-MPs from L. mexicana (LmGDP-MP), L. donovani (LdGDP-MP), and human (hGDP-MP), and compared their enzymatic properties. From a rationale design of 100 potential inhibitors, four compounds were identified having a promising and specific inhibitory effect on parasite GDP-MP and antileishmanial activities, one of them exhibits a competitive inhibition on LdGDP-MP and belongs to the 2-substituted quinoline series.

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“…A high-throughput screening (HTS) assay, using a library of about 80,000 compounds, has recently been set up in order to select GDP-MP inhibitors (Lackovic et al , 2010). From this study, some inhibitors exhibited an in vitro activity on Leishmania GDP-MP and on intracellular parasite proliferation confirming the relevance of this target for drug design.…”

Section: Introductionmentioning

confidence: 99%

In silicoanalysis of a therapeutic target inLeishmania infantum: the guanosine-diphospho-D-mannose pyrophosphorylase

et al. 2012

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Leishmaniases are tropical and sub-tropical diseases for which classical drugs (i.e. antimonials) exhibit toxicity and drug resistance. Such a situation requires to find new chemical series with antileishmanial activity. This work consists in analyzing the structure of a validated target in Leishmania: the GDP-mannose pyrophosphorylase (GDP-MP), an enzyme involved in glycosylation and essential for amastigote survival. By comparing both human and L. infantum GDP-MP 3D homology models, we identified (i) a common motif of amino acids that binds to the mannose moiety of the substrate and, interestingly, (ii) a motif that is specific to the catalytic site of the parasite enzyme. This motif could then be used to design compounds that specifically inhibit the leishmanial GDP-MP, without any effect on the human homolog.

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Inhibitors of Leishmania GDP-Mannose Pyrophosphorylase Identified by High-Throughput Screening of Small-Molecule Chemical Library

Cited by 39 publications

References 29 publications

In Vitro Activities of New 2-Substituted Quinolines against Leishmania donovani

In Vitro Activities of New 2-Substituted Quinolines against Leishmania donovani

Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads

In silicoanalysis of a therapeutic target inLeishmania infantum: the guanosine-diphospho-D-mannose pyrophosphorylase

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