Blood-stage antiplasmodial activity and oocyst formation-blockage of metallo copper-cinchonine complex

In the fight against malaria, the key is early treatment with antimalarial chemotherapy, such as artemisinin-based combination treatments (ACTs). However, Plasmodium has acquired multidrug resistance, including the emergence of P. falciparum strains with resistance to ACT. The development of novel antimalarial molecules, that are capable of interfering in the asexual and sexual blood stages, is important to slow down the transmission in endemic areas. In this work, we studied the ability of the mettalo copper-cinchonine complex to interfere in the sexual and asexual stages of Plasmodium. The tested compound in the in vitro assay was a cinchonine derivative, named CinCu (Bis[Cinchoninium Tetrachlorocuprate(II)]trihydrate). Its biological functions were assessed by antiplasmodial activity in vitro against chloroquine-resistant P. falciparum W2 strain. The mice model of P. berghei ANKA infection was used to analyze the antimalarial activity of CinCu and chloroquine and their acute toxicity. The oocyst formation-blocking assay was performed by experimental infection of Anopheles aquasalis with P. vivax infected blood, which was treated with different concentrations of CinCu, cinchonine, and primaquine. We found that CinCu was able to suppress as high as 81.58% of parasitemia in vitro, being considered a molecule with high antiplasmodial activity and low toxicity. The in vivo analysis showed that CinCu suppressed parasitemia at 34% up to 87.19%, being a partially active molecule against the blood-stage forms of P. berghei ANKA, without inducing severe clinical signs in the treated groups. The transmission-blocking assay revealed that both cinchonine and primaquine were able to reduce the infection intensity of P. vivax in A. aquasalis, leading to a decrease in the number of oocysts recovered from the mosquitoes’ midgut. Regarding the effect of CinCu, the copper-complex was not able to induce inhibition of P. vivax infection; however, it was able to induce an important reduction in the intensity of oocyst formation by about 2.4 times. It is plausible that the metallo-compound also be able to interfere with the differentiation of parasite stages and/or ookinete-secreted chitinase into the peritrophic matrix of mosquitoes, promoting a reduction in the number of oocysts formed. Taken together, the results suggest that this compound is promising as a prototype for the development of new antimalarial drugs. Furthermore, our study can draw a new pathway for repositioning already-known antimalarial drugs by editing their chemical structure to improve the antimalarial activity against the asexual and sexual stages of the parasite

Produção de maracujazeiro-amarelo sob diferentes densidades de plantio

O adensamento de plantas em cultivos do maracujazeiro-amarelo é importante por propiciar maior rentabilidade em menor área. O objetivo deste trabalho foi avaliar o efeito de diferentes densidades de plantio na produção, qualidade dos frutos e rentabilidade do maracujazeiro-amarelo. O experimento foi instalado e conduzido em pomar comercial da Fazenda Sant'ana, Município de São Tiago, MG. O delineamento experimental utilizado foi o de blocos casualizados com cinco tratamentos e quatro repetições. Os tratamentos constituíram-se de diferentes espaçamentos na linha de plantio: T1, 1,0 m (3.330 plantas/ha); T2, 1,5 m (2.220 plantas/ha); T3, 2,0 m (1.660 plantas/ha); T4, 3,0 m (1.100 plantas/ha) e T5, 4,0 m (830 plantas/ha). O espaçamento entre linhas foi de 3,0 m em todos os tratamentos. Cada parcela foi constituída de 12 m de comprimento por 3,0 m de largura (36 m²). O plantio foi realizado em outubro de 2001, e a colheita, a partir de abril, estendendo-se até agosto de 2002. A maior produtividade foi estimada em 11,9 t/ha na densidade de 1.841 plantas/ha. O adensamento não altera a qualidade do fruto. A máxima eficiência econômica foi alcançada na densidade de 1.340 plantas/ha, com rentabilidade de R$ 1.321,92/ha

Parâmetros genéticos e análise de trilha para o florescimento precoce e características agronômicas da alface

O objetivo deste trabalho foi avaliar os parâmetros genéticos das características agronômicas e de tolerância ao florescimento precoce de onze cultivares de alface, bem como verificar a existência de associação entre as características. O experimento foi realizado em ambiente protegido, em delineamento de blocos ao acaso, com quatro repetições e doze plantas por parcela. Quarenta e cinco dias após o transplantio das mudas, foram mensuradas as seguintes características: massa de matéria fresca total e "comercial" da parte aérea, massa de matéria seca "comercial" da parte aérea, massa de matéria fresca e seca da raiz, diâmetro e circunferência da cabeça, altura de planta, número de folhas por planta e número de dias até a antese. Há variabilidade genética entre as cultivares, em todas as variáveis, exceto quanto à circunferência de planta e matéria fresca da raiz. As cultivares Regina 500, Lívia e Atração foram superiores quanto ao número de dias para o florescimento e também para as demais características avaliadas. A seleção contra o florescimento precoce ocasionou ganho em todas as características; porém, não interferiu na matéria seca da raiz. A matéria fresca da parte aérea e o diâmetro de cabeça são indicadas para a seleção indireta contra o florescimento precoce

New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

Background: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. Methods: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. Results: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3–71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. Conclusion: The investigated, trioxolane–tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.info:eu-repo/semantics/publishedVersio

Antiplasmodial activity of aryltetralone lignans from Holostylis reniformis

Extracts from Holostylis reniformis were tested in vivo against Plasmodium berghei and in vitro against a chloroquine-resistant strain of Plasmodium falciparum. The hexane extract of the roots was the most active, causing 67% reduction of parasitemia in vivo. From this extract, six lignans, including a new (7 ' R,8S,8 ' S)-3 ',4 '-methylenedioxy-4,5-dimethoxy-2,7 '-cyclolignan-7-one, were isolated and tested in vitro against P. falciparum. The three most active lignans showed 50% inhibitor concentrations of <= 0.32 mu M. An evaluation of minimum lethal dose (30%) values showed low toxicity for these lignans in a hepatic cell line (Hep G2A16). Therefore, these compounds are potential candidates for the development of antimalarial drugs

Cytotoxicity, hemolysis and in vivo acute toxicity of 2-hydroxy-3-anilino-1,4-naphthoquinone derivatives

The 1,4-naphthoquinones, important members of the family of quinones are used as both crude extracts and as compound manipulated by the pharmaceutical industry. They have gained great emphasis by presenting different pharmacological properties as antibacterial, antiviral, antiprotozoal and anthelmintic, and has antitumor activity. Our aim was to evaluate the cytotoxicity, hemolytic activity and in vivo acute toxicity of three derivatives of 2-hydroxy-1,4-naphthoquinones. The cell viability in vitro against RAW Cell Line displayed IC50 ranging of 483.5–2044.8 μM, whereas in primary culture tests using murine macrophages, IC50 were 315.8–1408.0 μM for naphthoquinones derivatives 4a and 4c respectively, besides no hemolysis was observed at the dose tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioral toxicity up to 300 mg/kg, and at a dose of 1000 mg/kg the derivatives not triggering signs of toxicity although the compound 4a have promoted hepatic steatosis and hyperemia in kidney tissue. Thereby, these modifications decrease the toxicity of the tested derivatives naphthoquinones, providing a high potential for the development of news drugs. Keywords: Naphthoquinones, Cytotoxicity, Hemolytic activity, Acute toxicit

Oral and Intragastric: New Routes of Infection by Leishmania braziliensis and Leishmania infantum?

Although Leishmania transmission in nature is associated with the bite of an infected sandfly vector, other possible transmission routes are speculated to occur, such as the oral route. We evaluated the possibility of infection by this route in golden hamsters (Mesocricetus auratus) using Leishmania braziliensis (Lb) and Leishmania infantum (Li). Hamsters were exposed to experimental oral or intragastrical infection with axenic promastigotes, besides oral ingestion of a suspension of cultivated macrophages infected with amastigotes, lesion-fed Lutzomyia longipalpis, skin lesion or infective spleen fragment. The parasite&rsquo;s isolation, besides a positive PCR and IFAT, confirmed the intragastric infection by promastigote parasites. The oral ingestion of macrophages infected with L. braziliensis amastigotes was also infective. These results confirmed that Leishmania parasites could infect mammals by the intragastric route through the ingestion of promastigote forms (what can happen after a sandfly ingestion) and by the oral ingestion of infected macrophages (what can happen in nature in a predator&ndash;prey interaction). The better understanding of these alternative routes is essential to understand their transmission dynamics in nature. As far as we know, this is the first time that oral and intragastric Leishmania transmission has been experimentally demonstrated, constituting new infection routes, at least for L. infantum and L. braziliensis

In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

Abstract Background Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones. Results The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol. Conclusions These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host

Comparative Study on the Antioxidant and Anti-Toxoplasma Activities of Vanillin and Its Resorcinarene Derivative

A resorcinarene derivative of vanillin, resvan, was synthesized and characterized by spectroscopic techniques. We measured the cytotoxicity (in vivo and in vitro), antioxidant and anti-Toxoplasma activities of vanillin and the resorcinarene compound. Here we show that vanillin has a dose-dependent behavior with IC50 of 645 µg/mL through an in vitro cytotoxicity assay. However, we could not observe any cytotoxic response at higher concentrations of resvan (IC50 &gt; 2,000 µg/mL). The in vivo acute toxicity assays of vanillin and resvan exhibited a significant safety margin indicated by a lack of systemic and behavioral toxicity up to 300 mg/kg during the first 30 min, 24 h or 14 days after administration. The obtained derivative showed greater antioxidative activity (84.9%) when comparing to vanillin (19.4%) at 1,000 μg/mL. In addition, vanillin presents anti-Toxoplasma activity, while resvan does not show that feature. Our findings suggest that this particular derivative has an efficient antioxidant activity and a negligible cytotoxic effect, making it a potential target for further biological investigations