naphthoquinones and Leishmaniasis

Topics: Animals; Chagas Disease; Leishmaniasis; Naphthoquinones; Trypanosoma brucei brucei; Trypanosoma cruzi

Leishmaniasis affects more than 12 million people in 98 countries, the infection being caused by more than 20 species of protozoan parasites belonging to the genus Leishmania and spread by sandflies bite. Poor sanitary conditions, malnutrition, deforestation and urbanization increase the risk for leishmaniasis. Leishmaniasis is the only tropical disease treated with non-anti-leishmanial drugs, among which liposomal amphotericin B, a combination of pentavalent antimonials and paromomycin and miltefosine, that are highly toxic, represent the most used ones. Drug resistance is now widespread and the search for new molecular targets is open. Topoisomerase 1B, that controls the topological state of DNA and is essential for the parasites viability, has been detected as a promising target for anti-leishmaniasis therapy. The enzyme presents structural/functional differences with the human counterpart, making it unique among Eukarya. Here we review the structural features of this enzyme and the drugs that can be developed and used for this specific targeting.

Topics: Antiprotozoal Agents; Camptothecin; DNA Topoisomerases, Type I; Humans; Indoles; Isoquinolines; Leishmania; Leishmaniasis; Naphthoquinones; Protozoan Proteins; Quercetin

Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activities of these substances for the development of drugs against the neglected diseases leishmaniasis and Chagas disease as well as malaria, tuberculosis and cancer. Three strategies used to develop bioactive naphthoquinoidal compounds are discussed: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Among these strategies, reactions such as copper-catalysed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, and heterocyclisations will be discussed for the development of naphthoquinoidal compounds against Trypanosoma cruzi, Leishmania and cancer. The aim of derivatisation is the generation of novel molecules that inhibit cellular organelles/processes, generate reactive oxygen species (ROS) and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against neglected diseases and cancer.

Topics: Animals; Cell Membrane; Chagas Disease; Humans; Hydrophobic and Hydrophilic Interactions; Leishmania; Leishmaniasis; Malaria; Naphthoquinones; Neoplasms; Reactive Oxygen Species; Trypanosoma cruzi; Tuberculosis

Topics: Animals; Antiprotozoal Agents; Excipients; Female; Leishmania; Leishmaniasis; Mice; Mice, Inbred BALB C; Micelles; Naphthoquinones; Poloxamer; Treatment Outcome

This study aimed to describe the preparation and in vitro evaluation of a surface-modified nanostructured lipid carrier (NLC) using chitosan and dextran for co-delivery of buparvaquone (BPQ) and polymyxin B (PB) against leishmaniasis.. The NLC was prepared using high-pressure homogenisation. Polymyxin B binding and surface modification with biopolymers were achieved by electrostatic interaction. In vitro cytotoxicity was assessed in mouse peritoneal macrophages, and leishmanicidal activity in amastigotes of Leishmania infantum.. The developed NLC proved to be a promising formulation with which to overcome the drawbacks of current leishmaniasis treatment by the co-delivery of two alternative drugs and a macrophage targeting modified surface.

Topics: Anti-Bacterial Agents; Biopolymers; Chitosan; Dextrans; Drug Combinations; Drug Delivery Systems; Leishmania infantum; Leishmaniasis; Lipids; Nanostructures; Naphthoquinones; Particle Size; Polymyxin B; Thermogravimetry

Atovaquone, an antiparasitic agent, could possibly represent an alternative therapy after relapse following classical treatment for visceral leishmaniasis. Atovaquone-resistant strains were selected in vitro by stepwise drug pressure to study the mechanism of resistance in Leishmania. Characteristics of a promastigote strain resistant to 250 microg/ml of atovaquone were compared with those of the wild type (WT) strain. Resistant strains were shown to have a high level of resistance (45 times). They were stable in drug-free medium for 6 months, and showed no cross-resistance with other antileishmanial drugs. Rhodamine uptake and efflux were studied. They were not modified in the resistant strain, indicating the absence of P-glycoprotein overexpession. The effect of atovaquone on membrane lipidic composition was determined in both WT and atovaquone-resistant promastigotes. Analysis of lipid composition of the atovaquone-resistant strain showed that sterol biosynthesis was decreased in atovaquone-resistant parasites. Cholesterol was found to be the major membrane sterol as opposed to the WT strain. Cholesterol, due to its ordering effect, could decrease membrane fluidity and subsequently block the passage of atovaquone through the membrane. Increased membrane cholesterol content and altered drug membrane fluidity resulted from possible decrease of ergosterol biosynthesis by atovaquone, incorporation of cholesterol by promastigotes in the culture medium, solubilisation of atovaquone by cholesterol and co-passage of the two compounds or influence of dimethylsulfoxide. These results indicate that different cellular alterations may participate in the resistant phenotype, by altering drug membrane permeability.

Topics: Animals; Antiprotozoal Agents; Atovaquone; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Membrane; Cholesterol; Dose-Response Relationship, Drug; Drug Resistance; Fatty Acids; Leishmania infantum; Leishmaniasis; Naphthoquinones; Rhodamines; Time Factors

A series of monomeric and dimeric naphthoquinones with potential for treatment of Leishmania infections was identified in vitro using both a direct cytotoxicity assay against extracellular promastigotes of Leishmania donovani, Leishmania infanturn, Leishmania enriettii, and Leishmania major and a test against intracellular amastigote L. donovani residing within murine macrophages. Several naphthoquinones proved to be active at concentrations in the microgram range (EC(50) 0.9-17.0 microg/ml). When tested against a panel of human cancer cell lines (KB, SKMel, A549, MDA) and murine bone marrow culture-derived macrophages (BMMPhi) as mammalian host cell controls, compounds with anti-Leishmania-activity showed moderate (EC(50)>25 microg/ml) to pronounced (EC(50)<10 microg/ml) toxic effects.

Topics: Animals; Humans; Leishmania; Leishmania donovani; Leishmania enriettii; Leishmania infantum; Leishmania major; Leishmaniasis; Macrophages; Naphthoquinones; Tumor Cells, Cultured

Topics: Animals; Antiprotozoal Agents; Chlorpromazine; Clofazimine; Electron Transport; Leishmania donovani; Leishmania mexicana; Leishmaniasis; Leishmaniasis, Visceral; Methylene Blue; Methylphenazonium Methosulfate; Mice; Mice, Inbred BALB C; Naphthoquinones; Nifurtimox; Vitamin K