Design, synthesis and antileishmanial in vitro activity of new series of chalcones-like compounds: a molecular hybridization approach.

The chalcone-like series 1a-1g was efficiently synthesized from Morita-Baylis-Hillman reaction (52-74% yields). Compounds 1a-1g were designed by molecular hybridization based on the anti-inflammatory drug methyl salicylate (3) and the antileishmanial moiety of the Morita-Baylis-Hillman adducts 2a-2g. The 1a-1g compounds were much more actives than precursor series 2a-2g, for example, IC(50)=7.65 µM on Leishmania amazonensis and 10.14 µM on Leishmania chagasi (compound 1c) when compared to IC(50)=50.08 µM on L. amazonensis and 82.29 µM on L. chagasi (compound 2c). The IC(50) values of compound 3 (228.49 µM on L. amazonensis and 261.45 µM on L. chagasi) and acryloyl salicylate 4 (108.50 µM on L. amazonensis and 118.83 µM on L. chagasi) were determined here, by the first time, on Leishmania.

Synthetic lapachol derivatives relax guinea-pig ileum by blockade of the voltage-gated calcium channels.

The present study was designed to further evaluate a possible spasmolytic activity of synthetic lapachol derivatives, norlapachol, alpha-norlapachone, beta-norlapachone and hydro-hydroxy-norlapachol (HH-norlapachol), on guinea-pig ileum. In guinea-pig ileum, except for norlapachol, all naphthoquinones inhibited the phasic contractions induced by carbachol or histamine. Even when the ileum was pre-contracted with KCl, carbachol or histamine, all naphthoquinones induced relaxation, suggesting that these naphthoquinones could be acting on the voltage-gated calcium channels (Ca(V)). As the tonic component this contraction is maintained mainly by the opening of the Ca(V), we hypothesized that these naphthoquinones might be acting on these channels. This hypothesis was confirmed by the observation that norlapachol (pD'2 = 4.99), alpha-norlapachone (pD'2 = 4.49), beta-norlapachone (pD'2 = 6.33), and HH-norlapachol (pD'2 = 4.53) antagonized the contractions induced by CaCl2 in depolarizing medium nominally without Ca2+. As beta-norlapachone was the most potent we decided to continue the study of its action mechanism. The fact that this naphthoquinone has inhibited the tonic contractions induced by S-(-)-Bay K8644 [EC50 = (1.6 +/- 0.30) x 10(-5) M] suggests that the Ca2+ channel involved belongs to the type L (Ca(V)1.2). In addition, in the functional level, the spasmolytic effect of beta-norlapachone does not involve participation of free radicals, since its curve of relaxation was unchanged in the presence of glutathione, an antioxidant agent.

Efficient synthesis of 16 aromatic Morita-Baylis-Hillman adducts: Biological evaluation on Leishmania amazonensis and Leishmania chagasi.

Sixteen aromatic Morita-Baylis-Hillman adducts (MBHA) 1-16 were efficiently synthesized in a one step Morita-Baylis-Hillman reaction (MBHR) involving commercial aldehydes with methyl acrylate or acrylonitrile (81-100% yields) without the formation of side products on DABCO catalysis and at low temperature (0°C). The toxicities of these compounds were assessed against promastigote form of Leishmania amazonensis and Leishmania chagasi. The low synthetic cost of these MBHA, green synthetic protocols, easy one-step synthesis from commercially available and cheap reagents as well as the very good antileishmanial activity obtained for 14 and 16 (IC50 values of 6.88µgmL⁻¹ and 11.06µgmL⁻¹ respectively on L. amazonensis; 9.58µgmL⁻¹ and 14.34µgmL⁻¹ respectively on L. chagasi) indicates that these MBHA can be a novel and promising class of anti-parasitic compounds.

Improved synthesis of seven aromatic Baylis-Hillman adducts (BHA): evaluation against Artemia salina Leach. and Leishmania chagasi.

We described a very efficient procedure to prepare seven aromatic compounds (1-7), a new class of antileishmanial substances, through Baylis-Hillman reaction (BHR). With one, all the Baylis-Hillman adducts were prepared in quantitative yields by reaction of the corresponding aromatic aldehydes in acrylonitrile at 0 degrees C in only 10-40min reaction time. We present our results about the toxicities of these compounds evaluated on the microcrustaceous Artemia salina Leach. and against promastigote Leishmania chagasi. All substances evaluated in this work have showed high bioactivity. The 3-hydroxy-2-methylene-3-(4-bromopheny)propanenitrile (4) (LC(50)=30.9 microg/mL on A. salina; IC(50)=25.2 microM on L. chagasi) was the most active compound evaluated on A. salina Leach. and on promastigote L. chagasi. The 2-[hydroxy(pyridin-4-yl)methyl]acrylonitrile (7) (LC(50)=30.9 microg/mL on A. salina Leach.; IC(50)=4.8 microg/mL on L. chagasi) was also a very active substance evaluated in this work on promastigote L. chagasi.

Molluscicidal activity of 2-hydroxy-[1, 4]naphthoquinone and derivatives

The toxic profile of lawsone (2-hydroxy-[1,4]naphthoquinone) and a series of [1,4]naphthoquinone derivatives was evaluated against the brine shrimp Artemia salina and against the mollusk Biomphalaria glabrata, the main transmitting vector of schistosomiasis in Brazil. Of the seventeen compounds tested nine fell below the threshold of 100 µg/mL set for potential molluscicidal activity by the World Health Organization. As a general rule derivatives with non-polar substituents presented the highest molluscicidal activities. These substances showed significant toxicity in A. salina lethality bioassay.

A toxicidade da lausona (2-hidroxi-1,4)-naftoquinona e de diversos derivados foi avaliada frente à Artemia salina e ao molusco Biomphalaria glabrata, o principal vetor de transmissão da esquistossomose no Brasil. Entre os dezessete compostos testados, nove apresentaram um perfil de toxicidade menor que 100 µg/mL, sendo potenciais agentes moluscicidas de acordo com as designações da Organização Mundial da Saúde. No presente estudo, os compostos contendo substituintes apolares exibiram as maiores atividades. Estes compostos também se mostraram significantemente tóxicos frente à A. salina.

Molluscicidal activity of 2-hydroxy-[1,4]naphthoquinone and derivatives.

The toxic profile of lawsone (2-hydroxy-[1,4]naphthoquinone) and a series of [1,4]naphthoquinone derivatives was evaluated against the brine shrimp Artemia salina and against the mollusk Biomphalaria glabrata, the main transmitting vector of schistosomiasis in Brazil. Of the seventeen compounds tested nine fell below the threshold of 100 microg/mL set for potential molluscicidal activity by the World Health Organization. As a general rule derivatives with non-polar substituents presented the highest molluscicidal activities. These substances showed significant toxicity in A. salina lethality bioassay.

Atividade antimicrobiana "in vitro" e determinação da concentração inibitória mínina (CIM) de fitoconstituintes e produtos sintéticos sobre bactérias e fungos leveduriformes / In vitro antimicrobial activity and determination of the minimum inhibitory concentration (MIC) of natural and synthetic compounds against bacteria and leveduriform fungi

Diante da problemática da resistência microbiana as pesquisas apontam para o uso de novos antibióticos que sejam eficazes ante os patógenos emergentes. Este trabalho objetiva testar frente a bactérias gram-positivas (Staphylococcus aureus), bactérias gram-negativas (Escherichia coli e Pseudomonas aeruginosa) e fungos leveduriformes (Candida albicans), a atividade antimicrobiana e a concentração inibitória mínima (CIM) de fitoconstituintes de Ocotea duckei Vattimo, do lapachol, seus derivados semi-sintéticos, alfa-lapachona, beta-nor-lapachona, beta-lapachona, alfa-nor-lapachona, beta-3-iodo-lapachona e alfa-3-iodo-lapachona, assim como 07 derivados nitrogenados obtidos a partir do lapachol por semi-síntese e de imidas cíclicas similares ao alcalóide filantimida. Os resultados obtidos estimulam o aprofundamento dos estudos para algumas dessas substâncias a exemplo do lapachol e seus análogos que demonstraram atividade antimicrobiana, de modo que os produtos que se apresentaram ativos para S. aureus, foram lapachol e o extrato etanólico de Ocotea duckei, para E. coli foi a iangambina e para a Candida albicans foram as imidas. As demais substâncias não apresentaram atividade antimicrobiana para as cepas testadas.

Regarding the problem of microbial resistance, the researches point to the use of new antibiotic which can be active against the emergent pathogens. This work aims to test the activity against Gram-positive bacteria (Staphylococcus aureus), Gram-negative bacteria (Escherichia coli e Pseudomonas aeruginosa) and leveduriform fungi (Candida albicans), and also the Minimum Inhibitory Concentration (MIC) of the constituent of Ocotea duckei Vattimo, lapachol and its synthetic derivatives alpha-lapachone, beta-nor-lapachone, beta-lapachone, alpha-nor-lapachone, beta-3-iodin-lapachone and alpha-3-iodin-lapachone, as well as seven nitrogenated derivatives of lapachol obtained through semi synthesis. The achieved results stimulate the deepening of the studies for some of theses substances such as lapachol and its analogous which demonstrated antimicrobial activity. The substances which were active against S. aureus, were lapachol and the ethanolic extract of Ocotea duckei Vattimo, against Escherichia coli iangambin and against C. albicans the imides. The other substances did not show any activity against the tested bacteria.

New 1,2,3,4-tetrahydro-1-aza-anthraquinones and 2-aminoalkyl compounds from norlapachol with molluscicidal activity.

New nitrogen derivatives from norlapachol, including four new diastereomeric 1,2,3,4-tetrahydro-1-aza-anthraquinones obtained from the Prins cyclization on suitable aminoacetaldehyde dimethylacetal derivatives with formic acid, were found to exhibit molluscicidal activity against Biomphalaria glabrata. These derivatives showed low to medium LC(50) values, similar to those reported previously for the homologous series of nitrogen derivatives of lapachol. The toxicity profile against Artemia salina was also determined for all compounds.

Molluscicidal activity of synthetic lapachol amino and hydrogenated derivatives.

A series of new amino derivatives and a new partially hydrogenated derivative of the natural naphthoquinone lapachol were assayed for molluscicidal activity against Biomphalaria glabrata. These derivatives showed low to medium LC(50) values, and a 3.1 microg/mL value for the most potent derivative of the series. The toxicity is in agreement with the decrease of polar character of the tested compounds.