Synthesis of naphthofuranquinones with activity against Trypanosoma cruzi

Silva, Raphael S. F.; Costa, Elaine; Trindade, Úrsula L.T.; Teixeira, Daniel V.; Pinto, Maria de Carmo F.R.; Santos, Gustavo L.; Malta, V. R. S.; Simone, C. A. De; Pinto, Antônio V.; Castro, Solange L. de

doi:10.1016/j.ejmech.2005.12.006

Cited by 67 publications

(30 citation statements)

References 11 publications

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“…Notably, intravenous enoxacin was effective in once-a-day dosing of 25 mg/kg ( p = 0.03; 12 mice per group), whereas CAPE was not statistically effective in once-a-day dosing (unpublished data). Lapachol (150 mg/kg) was not active in the mouse model (unpublished data), consistent with previous work that suggested that lapachol may be transformed into inactive metabolite(s) or neutralized in mammals [36–38]. …”

Section: Resultssupporting

confidence: 89%

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Antifungal Chemical Compounds Identified Using a C. elegans Pathogenicity Assay

et al. 2007

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There is an urgent need for the development of new antifungal agents. A facile in vivo model that evaluates libraries of chemical compounds could solve some of the main obstacles in current antifungal discovery. We show that Candida albicans, as well as other Candida species, are ingested by Caenorhabditis elegans and establish a persistent lethal infection in the C. elegans intestinal track. Importantly, key components of Candida pathogenesis in mammals, such as filament formation, are also involved in nematode killing. We devised a Candida-mediated C. elegans assay that allows high-throughput in vivo screening of chemical libraries for antifungal activities, while synchronously screening against toxic compounds. The assay is performed in liquid media using standard 96-well plate technology and allows the study of C. albicans in non-planktonic form. A screen of 1,266 compounds with known pharmaceutical activities identified 15 (∼1.2%) that prolonged survival of C. albicans-infected nematodes and inhibited in vivo filamentation of C. albicans. Two compounds identified in the screen, caffeic acid phenethyl ester, a major active component of honeybee propolis, and the fluoroquinolone agent enoxacin exhibited antifungal activity in a murine model of candidiasis. The whole-animal C. elegans assay may help to study the molecular basis of C. albicans pathogenesis and identify antifungal compounds that most likely would not be identified by in vitro screens that target fungal growth. Compounds identified in the screen that affect the virulence of Candida in vivo can potentially be used as “probe compounds” and may have antifungal activity against other fungi.

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Section: Resultssupporting

confidence: 89%

“…Enoxacin, a fluoroquinolone antibiotic, was shown previously to marginally enhance the in vitro antifungal activity of amphotericin B and mepartricin [35]. Lapachol is a naphthoquinone found in the seeds and heartwood of tropical plants that exhibits anti-leishmanicidal activity [36–38]. Enoxacin did not inhibit C.…”

Section: Resultsmentioning

confidence: 99%

Antifungal Chemical Compounds Identified Using a C. elegans Pathogenicity Assay

et al. 2007

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“…TEM and flow cytometry data also showed primarily mitochondrial alterations in the amidine treated parasites (Silva et al 2006).…”

Section: Diamidines and Related Compoundsmentioning

confidence: 99%

“…Two derivatives were obtained by the addition of iodine to C-allyl-lawsone (2-hydroxy-3-allyl-naphthoquinone), followed by cyclisation to generate a furan ring; a third compound was obtained through an acid-catalysed reaction by dissolution of the original quinone in sulfuric acid. These compounds were active against the trypomastigote, intracellular amastigote and epimastigote forms presented low toxicity toward host mammalian cells and their chemical structure endowed them with redox properties, thus stimulating further studies (Silva et al 2006). Ultrastructural analysis of treated epimastigotes and trypomastigotes indicated potent effects of the three naphthofuranquinones in parasite mitochondria, which appeared drastically swollen and possessed a washedout matrix profile.…”

Section: Naphthoquinones and Derivativesmentioning

confidence: 99%

Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies

Soeiro

Dantas

Daliry

et al. 2009

Mem. Inst. Oswaldo Cruz

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“…10 Its homologue, 1,2-dihydro-2,2-dimethylbenzo[a]furo [2,3-c]phenazine, compound 10, is obtained from nor-β-lapachone 10a which was synthesized following the methods described in the literature (Figure 3). [12][13] The new monomethyl derived-phenazine 9 (Figure 2), submitted to m-CPBA oxidation has furnished two compounds: the 9-membered macrolactone N-oxide 11 and the α-hydroxy-ketone 12 ( Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Chemoselective oxidation of benzophenazines by m-CPBA: n-oxidation vs. oxidative cleavage

Silva

Amorim

Pinto

et al. 2007

J. Braz. Chem. Soc.

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Quimiosseletividade é observada, após reação de oxidação, utilizando-se m-CPBA, a partir da piranobenzo [a]fenazina e da furanobenzo [a]fenazina, derivadas, respectivamente da β-lapachona e da nor-β-lapachona. A fenazina pirânica forneceu macrolactonas, principalmente, enquanto a fenazina furânica conduziu a um único produto: o N-8 óxido da fenazina. Objetivando entender essa diferença de reatividade, uma nova fenazina furânica foi sintetizada, tendo como característica principal, a presença da ligação dupla em um sítio menos encoberto estericamente do que aquele presente no derivado nor-beta-lapachônico. Essa furanofenazina, após oxidação com m-CPBA, forneceu, principalmente, a macrolactona esperada. Esses resultados experimentais, aliados a cálculos mecânico-moleculares do estado fundamental dos substratos, permitiram sugerir que a quimiosseletividade observada pode ter controle estérico, relacionado à presença dos grupos substituintes metila geminados, que dificultam a aproximação do oxidante. Muitos dos compostos sintetizados são relatados, pela primeira vez, no presente artigo.Chemoselectivity is observed when a pyran-benzo[a]phenazine and a furanbenzo[a]phenazine from β-lapachone and nor-β-lapachone, respectively, were submitted to oxidation by m-CPBA. The pyran phenazine furnished mainly macrolactones, while the furan one led exclusively to a phenazine N-8 oxide. To understand this difference in reactivity, we synthesized a new furan phenazine, with the reactive double bond site less hindered than that of the derivative from nor-beta-lapachone. This furan phenazine, upon oxidation with m-CPBA, furnished mainly the expected macrolactone. These experimental results, along with preliminary analysis based on mechanical molecular calculations of the ground state of the substrates, allowed us to suggest that the observed chemoselectivity has a steric oxidant approach control origin, related to the presence of the geminal methyl groups in the phenazine structure. Several of the synthesized compounds are, herein, reported for the first time.

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Synthesis of naphthofuranquinones with activity against Trypanosoma cruzi

Cited by 67 publications

References 11 publications

Antifungal Chemical Compounds Identified Using a C. elegans Pathogenicity Assay

Antifungal Chemical Compounds Identified Using a C. elegans Pathogenicity Assay

Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies

Chemoselective oxidation of benzophenazines by m-CPBA: n-oxidation vs. oxidative cleavage

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