Antiparasitic and anti-inflammatory activities of ß-lapachone-derived naphthoimidazoles in experimental acute Trypanosoma cruzi infection

BACKGROUND Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from β-lapachone (N1, N2 and N3) being the most active in vitro. OBJECTIVES In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated. METHODS in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses. FINDINGS Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters. MAIN CONCLUSION N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.

ANTHELMINTIC ACTIVITY OF LAPACHOL, β-LAPACHONE AND ITS DERIVATIVES AGAINST Toxocara canis LARVAE / Atividade anti-helmíntica do lapachol, β-lapachona e derivados contra larvas de Toxocara canis

Anthelmintics used for intestinal helminthiasis treatment are generally effective; however, their effectiveness in tissue parasitosis (i.e. visceral toxocariasis) is moderate. The aim of this study was to evaluate the in vitro activity of lapachol, β-lapachone and phenazines in relation to the viability of Toxocara canis larvae. A concentration of 2 mg/mL (in duplicate) of the compounds was tested using microculture plates containing Toxocara canis larvae in an RPMI-1640 environment, incubated at 37 °C in 5% CO2 tension for 48 hours. In the 2 mg/mL concentration, four phenazines, lapachol and three of its derivatives presented a larvicide/larvistatic activity of 100%. Then, the minimum larvicide/larvistatic concentration (MLC) test was conducted. The compounds that presented the best results were nor-lapachol (MLC, 1 mg/mL), lapachol (MLC 0.5 mg/mL), β-lapachone, and β-C-allyl-lawsone (MLC, 0.25 mg/mL). The larvae exposed to the compounds, at best MLC with 100% in vitro activity larvicide, were inoculated into healthy BALB/c mice and were not capable of causing infection, confirming the larvicide potential in vitro of these compounds.

Os anti-helmínticos empregados no tratamento das helmintoses intestinais, de modo geral, são eficazes, porém nas parasitoses teciduais, como é o caso da toxocaríase visceral, a eficácia é moderada. Este estudo teve como objetivo avaliar in vitro a atividade do lapachol, β-lapachona e fenazinas derivadas da β-lapachona sobre a viabilidade de larvas de Toxocara canis. Os compostos foram testados na concentração de 2 mg/mL (em duplicata) em placas de microcultivo, contendo larvas de T. canis em meio RPMI-1640, sendo incubados, a 37 °C, em tensão de CO2 de 5%, por 48 horas. Na concentração de 2 mg/mL, quatro fenazinas, o lapachol e três derivados, apresentaram atividade larvicida/larvostática de 100%. A seguir, foi realizado o teste de concentração larvicida/larvostártica mínima (CLM). Os compostos que apresentaram os melhores resultados foram o nor-lapachol (CLM, 1 mg/mL), lapachol (CLM, 0,5 mg/mL), a β-lapachona e a β-C-alil-lausona (CLM, 0,25 mg/mL). As larvas expostas aos compostos, na melhor CLM 100% in vitro foram inoculadas em camundongos BALB/c saudáveis não sendo capazes de causar infecção, confirmando o potencial larvicida in vitro desses compostos.

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

Antiviral activity of naphthoquinones: I. Lapachol derivatives against enteroviruses

Some derivatives obtained by chemical transformation of lapachol (a natural substance extracted from the core of plants belonging to the family Bignoniaceae) vere studied as to their posible antiviral action. Cell cultures were treated with those substances and then inoculated with poliovirus type 1, echovirus 19 and Coxsackievirus B type 4. Only ß-lapachone, succinamidyl-ß-norlapachone and intermediary of Hooker have shown a significant viral inhibition index to echovirus type 19. Those derivatives had in in vitro ion but they did not cause any harm to the viral particles studied (virucidal action)