Antimalarial activity of phenazines from lapachol, β-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo

Andrade‐Neto, Valter Ferreira de; Goulart, Marília Oliveira Fonseca; Filho, Jorge F da Silva; Silva, Matuzalém J da; Pinto, Maria do Carmo F. R.; Pinto, Antônio V.; Zalis, Mariano Gustavo; Carvalho, Luzia H.; Krettli, Antoniana U.

doi:10.1016/j.bmcl.2003.12.069

Cited by 290 publications

(73 citation statements)

References 25 publications

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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). However, for 10, analysis of the reactional mixture pointed to the almost exclusive formation of the mono-N-oxide product (13), without any evidence of the formation of the corresponding 9-membered macrolactone ( Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…The product characterization was based on data from spectroscopic methods, mainly IR, 1 H NMR and 13 The differences in reactivity of these phenazines toward m-CPBA oxidation (1, 5, 6, and 9, Figures 1 and 2, which produced the corresponding macrolactones, versus 10, Figure 3, which led only to N-8 oxide product) has prompted us to perform some preliminary theoretical calculations on these substrates.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

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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“…Preparation of 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione (2). Yellow solution of lapazine, was prepared as described 4,9 (1; 314 mg; 1.0 mmol) in 20 mL of methylene chloride, treated with ozone at -5.0 o C until all substrate had reacted (1h).…”

Section: Methodsmentioning

confidence: 99%

“…Yellow solution of lapazine, was prepared as described 4,9 (1; 314 mg; 1.0 mmol) in 20 mL of methylene chloride, treated with ozone at -5.0 o C until all substrate had reacted (1h). The colourless reaction product was reduced with Zn/water and, after the usual workup, was submitted to silica gel column chromatography using hexane/ethyl acetate (95:5) as eluent.…”

Section: Methodsmentioning

confidence: 99%

“…O efeito de substituintes localizados no anel diidropirânico das fenazinas, no caso C2'-OH, C2'-Br e C2'-I, em reações de oxidação com MCPBA, foi também investigado.The benzophenazine from β-lapachone was submitted to ozonolysis under conditions that selectively furnished the corresponding rigid macrocyclic lactone 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione in an yield of 52%. The effect of substituents located at the dihydropyrane moiety of the phenazines, namely C2'-OH, C2'-Br and C2'-I, in the oxidation with MCPBA, was also investigated.…”

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confidence: 99%

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The preparation of a 10-membered ring macrolactone by selective ozonolysis and the role of the dihydropyran-substituent on the MCPBA-oxidation reaction profile of beta-lapachone phenazines

Silva¹,

Guimarães²,

Teixeira³

et al. 2005

J. Braz. Chem. Soc.

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A benzofenazina derivada da β-lapachona foi submetida a ozonólise em condições que forneceram seletivamente a lactona macrocíclica 7,7-dimetil-7,8,9,10-tetrahidro-5H-benzo[3,4]oxecino [5,6-b]quinoxalina-5,10-diona, com rendimento de 52%. O efeito de substituintes localizados no anel diidropirânico das fenazinas, no caso C2'-OH, C2'-Br e C2'-I, em reações de oxidação com MCPBA, foi também investigado.The benzophenazine from β-lapachone was submitted to ozonolysis under conditions that selectively furnished the corresponding rigid macrocyclic lactone 7,7-dimethyl-7,8,9,10-tetrahydro-5H-benzo [3,4]oxecino [5,6-b]quinoxaline-5,10-dione in an yield of 52%. The effect of substituents located at the dihydropyrane moiety of the phenazines, namely C2'-OH, C2'-Br and C2'-I, in the oxidation with MCPBA, was also investigated.Keywords: β-lapachone, ozonolysis, 10-membered ring macrolide, selectivity, effect of substituent IntroductionIn general, natural and synthetic phenazines have attracted considerable attention because of their interesting biological activities, 1 including broad-spectrum antibiotic, 2 antimalarial, 3,4 trypanocidal 5 along with anti hepatitis C viral replication activities.6 Benzo[a]phenazines are also efficient DNA intercalating ligands, exhibiting antitumor activity in leukaemia and solid tumors.7 They have also been described as dual inhibitors of topoisomerase I and II. 8 In our search for preparing new derivatives, for synthetic purposes and biological screening, we recently reported 9 that peroxidation of the b-lapachone-derived benzophenazine, named lapazine (1), with m-ClC 6 H 4 CO 2 H/CH 2 Cl 2 generated, unexpectedly, a macrocyclic lactone 2 with a rigid 10-membered ring (27% yield), the corresponding N-oxide 3 (13% yield), and the dihydrobenzophenazine-5-one 4 (35% yield) (Figure 1). Macrocyclic compounds 2 and 3 were formed via oxidative cleavage of the aromatic double bond at the site of fusion of the dihydropyran moiety with the phenazine component. This region (rings C/E, in 1) (Figure 1) would behave as a conjugated enol ether, which, after the expected epoxide formation and fragmentation would lead to 2 and 3 (further oxidation). An acid-catalysed epoxide-acetal or α-hydroxy hemiacetal would furnish 4. 9Compounds 2 and 3 belong to the class of macrolides, an important group of biologically active compounds, especially recognized as antibiotics. 10Among 10-membered macrolactones, the antibiotic activity of apicularen A and B was reported. 11In the present work, considering 2 and 3, the presence of diaza heterocyclic groups close to the ion-binding macrolactone moiety constitutes attractive molecular features.In searching for a more general application of the oxidative cleavage by MCPBA, 9 we have analysed the role of substituent, at C-2', in the dihydropyrane moiety of lapazine, namely -OH (5), -Br (6) and -I (7) (Figure 1). 1075 The Preparation of a 10-Membered Ring Macrolactone Vol. 16, No. 5, 2005 Additionally, in an attempt to develop a more selective and simpler method by...

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Chiral Squaramide‐Catalyzed Highly Enantioselective Michael Addition of 2‐Hydroxy‐1,4‐naphthoquinones to Nitroalkenes

Yang

2011

Adv Synth Catal

122

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A chiral squaramide-organocatalyzed, highly enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes has been developed. This reaction afforded the chiral naphthoquinones in excellent yields (up to 99%) and excellent enantioselectivity (up to 98% ee) under very low catalyst loading (0.25 mol%). This organocatalytic asymmetric Michael addition provides an efficient alternative route toward the synthesis of chiral functionalized naphthoquinones.

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Antimalarial activity of phenazines from lapachol, β-lapachone and its derivatives against Plasmodium falciparum in vitro and Plasmodium berghei in vivo

Cited by 290 publications

References 25 publications

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

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

The preparation of a 10-membered ring macrolactone by selective ozonolysis and the role of the dihydropyran-substituent on the MCPBA-oxidation reaction profile of beta-lapachone phenazines

Chiral Squaramide‐Catalyzed Highly Enantioselective Michael Addition of 2‐Hydroxy‐1,4‐naphthoquinones to Nitroalkenes

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