In vitro and in silico assessment of new beta amino ketones with antiplasmodial activity.

BACKGROUND: Based on the current need for new drugs against malaria, our study evaluated eight beta amino ketones in silico and in vitro for potential antimalarial activity. METHODS: Using the Brazilian Malaria Molecular Targets (BraMMT) and OCTOPUS® software programs, the pattern of interactions of beta-amino ketones was described against different proteins of P. falciparum and screened to evaluate their physicochemical properties. The in vitro antiplasmodial activities of the compounds were evaluated using a SYBR Green-based assay. In parallel, in vitro cytotoxic data were obtained using the MTT assay. RESULTS: Among the eight compounds, compound 1 was the most active and selective against P. falciparum (IC50 = 0.98 µM; SI > 60). Six targets were identified in BraMMT that interact with compounds exhibiting a stronger binding energy than the crystallographic ligand: P. falciparum triophosphate phosphoglycolate complex (1LYX), P. falciparum reductase (2OK8), PfPK7 (2PML), P. falciparum glutaredoxin (4N0Z), PfATP6, and PfHT. CONCLUSIONS: The physicochemical properties of compound 1 were compatible with the set of criteria established by the Lipinski rule and demonstrated its potential as a drug prototype for antiplasmodial activity.

In vitro and in silico assessment of new beta amino ketones with antiplasmodial activity

ABSTRACT Background: Based on the current need for new drugs against malaria, our study evaluated eight beta amino ketones in silico and in vitro for potential antimalarial activity. Methods: Using the Brazilian Malaria Molecular Targets (BraMMT) and OCTOPUS® software programs, the pattern of interactions of beta-amino ketones was described against different proteins of P. falciparum and screened to evaluate their physicochemical properties. The in vitro antiplasmodial activities of the compounds were evaluated using a SYBR Green-based assay. In parallel, in vitro cytotoxic data were obtained using the MTT assay. Results: Among the eight compounds, compound 1 was the most active and selective against P. falciparum (IC50 = 0.98 µM; SI > 60). Six targets were identified in BraMMT that interact with compounds exhibiting a stronger binding energy than the crystallographic ligand: P. falciparum triophosphate phosphoglycolate complex (1LYX), P. falciparum reductase (2OK8), PfPK7 (2PML), P. falciparum glutaredoxin (4N0Z), PfATP6, and PfHT. Conclusions: The physicochemical properties of compound 1 were compatible with the set of criteria established by the Lipinski rule and demonstrated its potential as a drug prototype for antiplasmodial activity.

Antiplasmodial and Cytotoxic Activities of Toad Venoms from Southern Amazon, Brazil.

The drug-resistance of malaria parasites is the main problem in the disease control. The huge Brazilian biodiversity promotes the search for new compounds, where the animal kingdom is proving to be a promising source of bioactive compounds. The main objective of this study was to evaluate the antiplasmodial and cytotoxic activity of the compounds obtained from the toad venoms of Brazilian Amazon. Toad venoms were collected from the secretion of Rhinella marina and Rhaebo guttatus in Mato Grosso State, Brazil. The powder was extracted at room temperature, yielding 2 extracts (RG and RM) and a substance ('1') identified as a bufadienolide, named telocinobufagin. Growth inhibition, intraerythrocytic development, and parasite morphology were evaluated in culture by microscopic observations of Giemsa-stained thin blood films. Cytotoxicity was determined against HepG2 and BGM cells by MTT and neutral red assays. The 2 extracts and the pure substance ('1') tested were active against chloroquine-resistant Plasmodium falciparum strain, demonstrating lower IC50 values. In cytotoxic tests, the 2 extracts and substance '1' showed pronounced lethal effects on chloroquine-resistant P. faciparum strain and low cytotoxic effect, highlighting toad parotoid gland secretions as a promising source of novel lead antiplasmodial compounds.

[Natural infection with Leishmania infantum chagasi in Lutzomyia (Lutzomyia) longipalpis (Diptera: Psychodidae) sandflies captured in the municipality of Janaúba, State of Minas Gerais, Brazil]. / Infecção natural de Lutzomyia (Lutzomyia) longipalpis (Diptera: Psychodidae) por Leishmania infantum chagasi em flebotomíneos capturados no município de Janaúba, Estado de Minas Gerais, Brasil.

INTRODUCTION: Visceral leishmaniasis has been notified in nearly all states of Brazil, and particularly in the north of Minas Gerais, where the disease is endemic. The aim of this study was to detect natural infection of Lutzomyia longipalpis and, through the PCR/RFLP technique, identify Leishmania species found in sandflies in the municipality of Janaúba. METHODS: Using light traps, 1,550 females of L. longipalpis were caught and grouped into pools of 10 specimens to be subjected to DNA extraction and amplification, by means of generic PCR and cacophony. RESULTS: Out of the 155 pools, six were positive for Leishmania sp., and thus the infection rate in the municipality was 3.9%. Through PCR/RFLP, the digestion pattern among the positive samples was found to be similar to that of the reference strain of Leishmania chagasi (MHOM/BR/74/PP75). CONCLUSIONS: The detection of natural infection associated with studies on the epidemiology of visceral leishmaniasis suggests that L. longipalpis is involved in transmission of L. infantum chagasi in Janaúba, particularly in areas of intense transmission of visceral leishmaniasis.

Infecção natural de Lutzomyia (Lutzomyia) longipalpis (Diptera: Psychodidae) por Leishmania infantum chagasi em flebotomíneos capturados no município de Janaúba, Estado de Minas Gerais, Brasil / Natural infection with Leishmania infantum chagasi in Lutzomyia (Lutzomyia) longipalpis (Diptera: Psychodidae) sandflies captured in the municipality of Janaúba, State of Minas Gerais, Brazil

INTRODUÇÃO: A leishmaniose visceral tem sido notificada em quase todos os estados do Brasil, e principalmente no norte de Minas Gerais, onde a doença é endêmica. Este estudo visou detectar a infecção natural de Lutzomyia longipalpis e identificar através da técnica de PCR/RFLP a espécie de Leishmania encontrada nos flebotomíneos do município de Janaúba. MÉTODOS: Utilizando-se armadilhas luminosas, foram capturadas 1.550 fêmeas de L. longipalpis, que agrupadas em pool de 10 exemplares foram submetidas à extração e amplificação de DNA, através das técnicas de PCR genérico e cacofonia. RESULTADOS: Dos 155 pools, seis apresentaram-se positivos para Leishmania sp., sendo a taxa de infecção do município de 3,9 por cento. Através da PCR/RFLP determinou-se que o padrão de digestão das amostras positivas foi semelhante ao da cepa referência Leishmania chagasi (MHOM/BR/74/PP75). CONCLUSÕES: A detecção de infecção natural associada a estudos sobre a epidemiologia da LV sugere que L. longipalpis esteja envolvida na transmissão de L. infantum chagasi em Janaúba, principalmente nas áreas de intensa transmissão de LV.

INTRODUCTION: Visceral leishmaniasis has been notified in nearly all states of Brazil, and particularly in the north of Minas Gerais, where the disease is endemic. The aim of this study was to detect natural infection of Lutzomyia longipalpis and, through the PCR/RFLP technique, identify Leishmania species found in sandflies in the municipality of Janaúba. METHODS: Using light traps, 1,550 females of L. longipalpis were caught and grouped into pools of 10 specimens to be subjected to DNA extraction and amplification, by means of generic PCR and cacophony. RESULTS: Out of the 155 pools, six were positive for Leishmania sp., and thus the infection rate in the municipality was 3.9 percent. Through PCR/RFLP, the digestion pattern among the positive samples was found to be similar to that of the reference strain of Leishmania chagasi (MHOM/BR/74/PP75). CONCLUSIONS: The detection of natural infection associated with studies on the epidemiology of visceral leishmaniasis suggests that L. longipalpis is involved in transmission of L. infantum chagasi in Janaúba, particularly in areas of intense transmission of visceral leishmaniasis.