Synthesis and anti-Trypanosoma cruzi activity of ß-lapachone analogues.

The available chemotherapy for Chagas disease, caused by Trypanosoma cruzi, is unsatisfactory; therefore, there is an intense effort to find new drugs for the treatment of this disease. In our laboratory, we have analyzed the effect on bloodstream trypomastigotes of 16 new naphthoquinone analogues of ß-lapachone modified in the pyran ring, aiming to find a new prototype with high trypanocidal activity. The new compounds presented a broad spectrum of activity, and five of them presented IC(50)/24 h in the range of 22-63 µM, whereas ß-lapachone had a higher value of 391.5 ± 16.5 µM.

1,2-Dihydr-oxy-2-(3-methyl-but-2-en-yl)-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid monohydrate.

The title compound, C(15)H(16)O(5)·H(2)O, is an inter-mediate of the Hooker oxidation reaction, used for the synthesis of 2-hydr-oxy-3-(2-methyl-prop-1-en-yl)naphthalene-1,4-dione (nor-lapachol). The packing in the crystal structure is arranged by an O-H⋯O hydrogen-bonded network along the [100] and [010] directions. Each organic mol-ecule is linked to four other mol-ecules via the hydr-oxy groups. The water solvent mol-ecule is connected to carboxylic acid groups by three hydrogen bonds.

The trypanocidal activity of naphthoquinones: a review.

Naphthoquinones are compounds present in several families of higher plants. Their molecular structures confer redox properties, and they are involved in multiple biological oxidative processes. In folk medicine, especially among Indian populations, plants containing naphthoquinones have been employed for the treatment of various diseases. The biological redox cycle of quinones can be initiated by one electron reduction leading to the formation of semiquinones, unstable intermediates that react rapidly with molecular oxygen, generating free radicals. Alternatively, the reduction by two electrons, mediated by DT-diphorase, leads to the formation of hydroquinone. Lapachol, alpha-lapachone and beta-lapachone, which are isolated from the heartwood of trees of the Bignoniaceae family, are examples of bioactive naphthoquinones. In this review, we will discuss studies investigating the activity of these natural products and their derivatives in the context of the search for alternative drugs for Chagas disease, caused by Trypanosoma cruzi, a neglected illness that is endemic in Latin America.

Activities of naphthoquinones against Aedes aegypti (Linnaeus, 1762) (Diptera: Culicidae), vector of dengue and Biomphalaria glabrata (Say, 1818), intermediate host of Schistosoma mansoni.

Larvicidal (against Aedes aegypti Linnaeus, 1762) and molluscicidal (against Biomphalaria glabrata Say, 1818) activities of several natural and synthetic naphthoquinones were measured, with significant results. The best larvicidal compound is 3-bromojuglone, while the better molluscicides are 2-bromo- and 3-bromo-5-acetoxy-1,4-naphthoquinones together with the 3-bromo-5-methoxy derivative. The present results reinforce the potential use of substituted hydroxyquinones, their salts and halogenated quinones as very promising compounds against 4th instar larves of Aedes aegypti, the vector of dengue and against adult snail of Biomphalaria glabrata.

Inner reorganization during the radical-biradical transition in a nor-beta-lapachone derivative possessing two redox centers.

In this work, the electrochemical behaviour of an antitumoral nitro o-quinone derivative obtained from 3-bromo-nor-beta-lapachone was studied. Cyclic voltammetric experiments, in acetonitrile solution, revealed that both quinone and nitro functions are reduced independently as quasi-reversible one-electron transfer processes in this order. Depending on the reduction potential, a radical anion or a biradical dianion is obtained. The formation of these paramagnetic species was confirmed by performing in situ Electrochemical-Electron Spin Resonance (E-ESR) experiments. Analysis of the kinetics of electron transfer associated to those electron uptake processes, in terms of the Marcus-Hush-Levich model, revealed differences in the reorganization energy (lambda((k))) for both steps (lambda((I)): 1.07-1.11 eV; lambda((II)): 1.21-1.30 eV). By evaluating the conformations of the radical and biradical systems by calculations at the BLYP//TZVP level of theory, it was found that the inner component, for the second reduction process (lambda((II))) was approximately 72% of lambda((II)), reflecting modifications in the molecular structure during the radical anion-biradical dianion transition. This change is also reflected in the differences presented by line widths of the ESR signals of both electrogenerated radical and diradical species.

Tabebuia avellanedae naphthoquinones: activity against methicillin-resistant staphylococcal strains, cytotoxic activity and in vivo dermal irritability analysis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococcus infections are a worldwide concern. Currently, these isolates have also shown resistance to vancomycin, the last therapy used in these cases. It has been observed that quinones and other related compounds exhibit antibacterial activity. This study evaluated the antibacterial activity, toxicity and in vivo dermal irritability of lapachol extracted from Tabebuia avellanedae and derivatives against methicillin-resistant staphylococcal isolates. In addition, its mechanism of action was also analyzed. METHODS: The compounds beta-lapachone, 3-hydroxy beta N lapachone and alpha-lapachone were tested to determine the MIC values against methicillin-resistant S. aureus, S. epidermidis and S. haemolyticus strains, being the two last ones hetero-resistant to vancomycin. Experiments of protein synthesis analysis to investigate the naphthoquinones action were assessed. In vitro toxicity to eukaryotic BSC-40 African Green Monkey Kidney cell cultures and in vivo primary dermal irritability in healthy rabbits were also performed. RESULTS: The compounds tested showed antibacterial activity (MICs of 8, 4/8 and 64/128 microg/mL to beta-lapachone, 3-hydroxy beta N lapachone and alpha-lapachone, respectively), but no bactericidal activity was observed (MBC > 512 microg/mL for all compounds). Although it has been observed toxic effect in eukaryotic cells, the compounds were shown to be atoxic when applied as topic preparations in healthy rabbits. No inhibition of proteins synthesis was observed. CONCLUSION: Our results suggest that quinones could be used in topic preparations against wound infections caused by staphylococci, after major investigation of the pharmacological properties of the compounds. Studies about the use of these compounds on tumoral cells could be carried on, due to their effect in eukaryotic cells metabolism.

Synthesis of naphthofuranquinones with activity against Trypanosoma cruzi.

Four new naphthofuranquinones, obtained from 2-hydroxy-3-allyl-naphthoquinone (1) and nor-lapachol (2), have their structures established by physical and X-ray analysis and their activity evaluated against Trypanosoma cruzi. Compounds 3 and 4 were obtained by addition of iodine to 1 followed by cyclization generating a furan ring. Compound 5 was obtained through the acid-catalyzed reaction by dissolution of 1 in sulfuric acid. Compound 6 was synthesized by addition of bromine and aniline to 2. The IC(50)/24 h for 3-6 in assays with T. cruzi trypomastigotes was between 157 and 640 microM, while the value for crystal violet was 536.0 +/- 3.0 microM. Compounds 3-5 also inhibited epimastigote proliferation. The trypanocidal activity of the new naphthofuranquinones endowed with redox properties reinforces a rational approach in the chemotherapy of Chagas' disease.

A trypanocidal phenazine derived from beta-lapachone.

An intensive effort has been directed toward finding alternative drugs for treatment of Chagas' disease, caused by Trypanosoma cruzi, and prophylaxis of blood in endemic areas. Our research comprises the synthesis and trypanocidal screening of derivatives from naphthoquinones. Herein a new phenazine, obtained from the reaction of beta-lapachone with aniline, has its structure established by physical data and X-ray analysis. It was 9 times more active against T. cruzi trypomastigotes than crystal violet.

NBS bromination reactions of dihydronaphthofuran quinones: a new fragmentation type reaction in the chemistry of quinones

The reactions of isomeric dilydronaphthofuran-quinones of the alfa ß type, 1 and 5, respectively, with NBS, under visible light, gave products. These reactions represent a new route to structural types represented by naphthol [1,2-b] furan and naphtho [2,3-b] furan quinones and lead to a new assessment of biosynthetic theory concerning the furan ring in plants

Seleçäo por meio de células KB de substâncias e extratos potencialmente ativos em quimioterapia do câncer / Selection by means of KB cells of substances and extracts potentially active in cancer chemotherapy

Several synthetic, semi-synthetic and natural compounds as well extracts were screened for their growht inhibition activity on KB cells. The most active ones were naphthoquinones and derivatives of pyrido [4,3-b] carbazole alkaloids, with inhibition dose (ID50) < 4microng/ml. Of the crude extracts of several plants screened, Vellozia caput-ardeae showed to be the most active

Atividade antivirótica de naftoquinonas: II. Derivados 1,4-naftoquinônicos frente a enterovírus

Foram estudadas 15 substâncias de estrutura naftoquinônica obtidas de síntese química: a própria 1,4-naftoquinona sem substituintes, um derivado com um radical hidroxila na posiçäo 2 e 13 derivados hidroxilados apresentando diferentes grupos metileno-amino na posiçäo 3. As culturas de células foram protegidas com as drogas antes da titulaçäo dos vírus (pólio 1, Coxackie B4 e ECHO 19). Pela determinaçäo do índice de inibiçäo virótico (IIV) mostrou-se que o ECHO-vírus 19 foi o mais inibido. Dos 14 compostos testados, 3 deles mostraram um IIV significativo contrao ECHO-vírus como segue: IIV de 1,75 para 2-HO-1,4-naftoquinina e 2-HO-3 (N-morfolil)-metil-1, 4-naftoquinona e IIV de 3,75 para 2-HO-3-N-benzil-N'(N-benzil-2-etilamina) -1,4-naftoquinona. Este último composto mostrou atividade virucida, em experiência paralela, significando que a droga afeta diretamente a partícula viral