Synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing anti-trypanosomal and anti-leishmanial activity

Bolognesi, María Laura; Lizzi, Federica; Perozzo, Remo; Brun, Reto; Cavalli, Andrea

doi:10.1016/j.bmcl.2008.03.009

Cited by 79 publications

(97 citation statements)

References 15 publications

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“…Among the 45 compounds that were potent against LmCK1.2, we identified several inhibitors described to have antileishmanial activity, including known CK1 inhibitors, such as anthraquinone (35)(36)(37), or compounds for which we revealed CK1 as a new target, such as gossypol, purpurogallin, and some flavonoids (38)(39)(40)(41)(42)43). These compounds, identified from several libraries, were found at least twice with similar IC 50 s, indicating that our assay is reproducible (data not shown).…”

Section: Resultsmentioning

confidence: 80%

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

Durieu

Prina

Olivier

et al. 2016

Antimicrob Agents Chemother

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h Existing therapies for leishmaniases present significant limitations, such as toxic side effects, and are rendered inefficient by parasite resistance. It is of utmost importance to develop novel drugs targeting Leishmania that take these two limitations into consideration. We thus chose a target-based approach using an exoprotein kinase, Leishmania casein kinase 1.2 (LmCK1.2) that was recently shown to be essential for intracellular parasite survival and infectivity. We developed a four-step pipeline to identify novel selective antileishmanial compounds. In step 1, we screened 5,018 compounds from kinase-biased libraries with Leishmania and mammalian CK1 in order to identify hit compounds and assess their specificity. For step 2, we selected 88 compounds among those with the lowest 50% inhibitory concentration to test their biological activity on host-free parasites using a resazurin reduction assay and on intramacrophagic amastigotes using a high content phenotypic assay. Only 75 compounds showed antileishmanial activity and were retained for step 3 to evaluate their toxicity against mouse macrophages and human cell lines. The four compounds that displayed a selectivity index above 10 were then assessed for their affinity to LmCK1.2 using a target deconvolution strategy in step 4. Finally, we retained two compounds, PP2 and compound 42, for which LmCK1.2 seems to be the primary target. Using this four-step pipeline, we identify from several thousand molecules, two lead compounds with a selective antileishmanial activity.

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Section: Resultsmentioning

confidence: 80%

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

Durieu

Prina

Olivier

et al. 2016

Antimicrob Agents Chemother

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“…315,316 The total synthesis of 336 was achieved as illustrated in Scheme 72. The total synthesis started from coupling of 1,5-naphthalenediol mono-methoxymethyl (MOM) ether 329 with bromobenzoquinone 330 mediated by K 2 CO 3 in DMSO 317 to afford a C-O coupling product. Upon reduction of the quinone moiety, present in acetonitrile using aqueous Na 2 S 2 O 4 , the mono-triation was regioselectively proceeded resulting in the formation of compound 332.…”

mentioning

confidence: 99%

Total synthesis of natural products containing benzofuran rings

et al. 2017

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Research on natural products containing benzofuran has remarkably increased during the past few decades.Newly isolated natural products with complex structures are being studied, characterized and screened for possible biological activities. Several of such compounds have exhibited various biological activities, thus their total syntheses have attracted much attention from synthetic organic chemists. In this review, we aim to highlight the origins, structures, biological potencies, and synthetic approaches of those natural products bearing at least one benzofuran in their complex structures. Furthermore, we especially focus on the step in which this key heterocycle is installed during the total synthesis of a natural product as the desired target.

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“…[30] Eine solche Vorabinformation nutzten Cavalli und Mitarbeiter beim Entwurf einer Verbindungsbibliothek, die Aktivität gegen Trypanosomen und Leishmanien zeigen sollte. [31] Der Entwurf der Bibliothek sah vor, die Chinoneinheit natürlich vorkommender Naphthochinone als Grundgerüst für die Strukturvariationen zu verwenden.…”

Section: Eine Lapochol-inspirierte Naphthochinon-bibliothekunclassified

Die Synthese von naturstoffinspirierten Verbindungsbibliotheken

Kumar

Waldmann

2009

Angewandte Chemie

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Der Natur abgeschaut: Die Entwicklung vielstufiger stereoselektiver Synthesen eröffnet den Zugang zu naturstoffinspirierten Verbindungsbibliotheken mit carbo‐, oxa‐ und azacyclischen Gerüststrukturen, die vielversprechende Quellen für neue Reagentien in der medizinischen Chemie und der chemischen Biologie sind. Das Bild zeigt eine Sammlung von naturstoffinspirierten Molekülen (blau) mit ihren zugrundeliegenden Naturstoffen (gelb).magnified imageNaturstoffe und ihre Derivate und Analoga gehören zu den wichtigsten Quellen neuer Wirkstoffkandidaten und Reagentien für die chemische Biologie und medizinische Chemie. Hieraus leitet sich ein großer Bedarf an effizienten Synthesemethoden ab, die einen Zugang zu naturstoffabgeleiteten oder ‐inspirierten Verbindungsbibliotheken ermöglichen. Um solche Verfahren entwickeln und anwenden zu können, ist es erforderlich, die vielstufigen stereoselektiven Synthesemethoden, wie sie für Naturstoffsynthesen charakteristisch sind, auf die Verfahrensweisen beim Aufbau von Verbindungsbibliotheken zu übertragen und entsprechend anzupassen. Neue Entwicklungen bei der Synthese naturstoffinspirierter Bibliotheken aus carbocyclischen und heterocyclischen Gerüststrukturen zeigen klar auf, dass dieses Ziel erreicht werden kann. Die bereits erzielten Fortschritte haben den Weg für die Einbeziehung naturstoffinspirierter Verbindungsbibliotheken in die medizinische Chemie und die biochemische Forschung geebnet.

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Synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing anti-trypanosomal and anti-leishmanial activity

Cited by 79 publications

References 15 publications

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

Total synthesis of natural products containing benzofuran rings

Die Synthese von naturstoffinspirierten Verbindungsbibliotheken

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