ABSTRACT
We report the results of the stellar occultation by (UII) Umbriel on 2020 September 21. The shadow crossed the USA and Canada, and 19 positive chords were obtained. A limb parameter ...accounted for putative topographic features in the limb fittings. Ellipse fittings were not robust – only upper limits were derived for the true size/shape of a putative Umbriel ellipsoid. The adopted spherical solution gives radius = 582.4 ± 0.8 km, smaller/close to 584.7 ± 2.8 km from Voyager II. The apparent ellipse fit results in a true semi-major axis of 584.9 ± 3.8 km, semi-minor axis of 582.3 ± 0.6 km, and true oblateness of 0.004 ± 0.008 for a putative ellipsoid. The geometric albedo was pV = 0.26 ± 0.01. The density was ρ = 1.54 ± 0.04 g cm−3. The surface gravity was 0.251 ± 0.006 m s−2 and the escape velocity was 0.541 ± 0.006 km s−1. Upper limits of 13 and 72 nbar (at 1σ and 3σ levels, respectively) were obtained for the surface pressure of a putative isothermal CO2 atmosphere at T = 70 K. A milliarcsecond precision position was derived: α = 02h30m28${_{.}^{\rm s}}$84556 ± 0.1 mas, δ = 14o19′36″.5836 ± 0.2 mas. A large limb parameter of 4.2 km was obtained, in striking agreement with opposite Southern hemisphere measurements by Voyager II in 1986. Occultation and Voyager results indicate that the same strong topography variation in the surface of Umbriel is present on both hemispheres.
Malaria is an endemic disease that affected 229 million people and caused 409 thousand deaths, in 2019. Disease control is based on early diagnosis and specific treatment with antimalarial drugs ...since no effective vaccines are commercially available to prevent the disease. Drug chemotherapy has a strong historical link to the use of traditional plant infusions and other natural products in various cultures. The research based on such knowledge has yielded two drugs in medicine: the alkaloid quinine from Cinchona species, native in the Amazon highland rain forest in South America, and artemisinin from Artemisia annua, a species from the millenary Chinese medicine. The artemisinin-based combination therapies (ACTs), proven to be highly effective against malaria parasites, and considered as “the last bullet to fight drug-resistant malaria parasites,” have limited use now due to the emergence of multidrug resistance. In addition, the limited number of therapeutic options makes urgent the development of new antimalarial drugs. This review focuses on the antimalarial activities of 90 plant species obtained from a search using Pubmed database with keywords “antimalarials,” “plants” and “natural products.” We selected only papers published in the last 10 years (2011–2020), with a further analysis of those which were tested experimentally in malaria infected mice. Most plant species studied were from the African continent, followed by Asia and South America; their antimalarial activities were evaluated against asexual blood parasites, and only one species was evaluated for transmission blocking activity. Only a few compounds isolated from these plants were active and had their mechanisms of action delineated, thereby limiting the contribution of these medicinal plants as sources of novel antimalarial pharmacophores, which are highly necessary for the development of effective drugs. Nevertheless, the search for bioactive compounds remains as a promising strategy for the development of new antimalarials and the validation of traditional treatments against malaria. One species native in South America,
Ampelozyzyphus amazonicus
, and is largely used against human malaria in Brazil has a prophylactic effect, interfering with the viability of sporozoites in
in vitro
and
in vivo
experiments.
Several species of Aspidosperma (Apocynaceae) are used as treatments for human diseases in the tropics. Aspidosperma olivaceum, which is used to treat fevers in some regions of Brazil, contains the ...monoterpenoid indole alkaloids (MIAs) aspidoscarpine, uleine, apparicine, and N-methyl-tetrahydrolivacine. Using bio-guided fractionation and cytotoxicity testing in a human hepatoma cell line, several plant fractions and compounds purified from the bark and leaves of the plant were characterized for specific therapeutic activity (and selectivity index, SI) in vitro against the blood forms of Plasmodium falciparum.
The activity of A. olivaceum extracts, fractions, and isolated compounds was evaluated against chloroquine (CQ)-resistant P. falciparum blood parasites by in vitro testing with radiolabelled 3H-hypoxanthine and a monoclonal anti-histidine-rich protein (HRPII) antibody. The cytotoxicity of these fractions and compounds was evaluated in a human hepatoma cell line using a 3-4,5-dimethylthiazol-2-yl-2,5 diphenyl tetrazolium bromide (MTT) assay, and the SI was calculated as the ratio between the toxicity and activity. Two leaf fractions were tested in mice with Plasmodium berghei.
All six fractions from the bark and leaf extracts were active in vitro at low doses (IC50 < 5.0 μg/mL) using the anti-HRPII test, and only two (the neutral and basic bark fractions) were toxic to a human cell line (HepG2). The most promising fractions were the crude leaf extract and its basic residue, which had SIs above 50. Among the four pure compounds evaluated, aspidoscarpine in the bark and leaf extracts showed the highest SI at 56; this compound, therefore, represents a possible anti-malarial drug that requires further study. The acidic leaf fraction administered by gavage to mice with blood-induced malaria was also active.
Using a bio-monitoring approach, it was possible to attribute the anti-P. falciparum activity of A. olivaceum to aspidoscarpine and, to a lesser extent, N-methyl-tetrahydrolivacine; other isolated MIA molecules were active but had lower SIs due to their higher toxicities. These results stood in contrast to previous work in which the anti-malarial activity of other Aspidosperma species was attributed to uleine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several species of Aspidosperma plants are referred to as remedies for the treatment of malaria, especially Aspidosperma nitidum. Aspidosperma pyrifolium, also a medicinal plant, is used as a natural ...anti-inflammatory. Its fractionated extracts were assayed in vitro for activity against malaria parasites and for cytotoxicity.
Aspidosperma pyrifolium activity was evaluated against Plasmodium falciparum using extracts in vitro. Toxicity towards human hepatoma cells, monkey kidney cells or human monocytes freshly isolated from peripheral blood was also assessed. Anti-malarial activity of selected extracts and fractions that presented in vitro activity were tested in mice with a Plasmodium berghei blood-induced infection.
The crude stem bark extract and the alkaloid-rich and ethyl acetate fractions from stem extract showed in vitro activity. None of the crude extracts or fractions was cytotoxic to normal monkey kidney and to a human hepatoma cell lines, or human peripheral blood mononuclear cells; the MDL
values of all the crude bark extracts and fractions were similar or better when tested on normal cells, with the exception of organic and alkaloidic-rich fractions from stem extract. Two extracts and two fractions tested in vivo caused a significant reduction of P. berghei parasitaemia in experimentally infected mice.
Considering the high therapeutic index of the alkaloidic-rich fraction from stem extract of A. pyrifolium, it makes the species a candidate for further investigation aiming to produce a new anti-malarial, especially considering that the active extract has no toxicity, i.e., no mutagenic effects in the genototoxicity assays, and that it has an in vivo anti-malarial effect. In its UPLC-HRMS analysis this fraction was shown to have two major components compatible with the bisindole alkaloid Leucoridine B, and a novel compound, which is likely to be responsible for the activity against malaria parasites demonstrated in in vitro tests.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malaria, Chagas disease, and leishmaniasis are tropical diseases caused by protozoan parasites of the genera
,
and
, respectively. These diseases constitute a major burden on public health in several ...regions worldwide, mainly affecting low-income populations in economically poor countries. Severe side effects of currently available drug treatments and the emergence of resistant parasites need to be addressed by the development of novel drug candidates. Natural 2,5-Diketopiperazines (2,5-DKPs) constitute N-heterocyclic secondary metabolites with a wide range of biological activities of medicinal interest. Its structural and physicochemical properties make the 2,5-DKP ring a versatile, peptide-like, and stable pharmacophore attractive for synthetic drug design. In the present work, twenty-three novel synthetic 2,5-DKPs, previously synthesized through the versatile Ugi multicomponent reaction, were assayed for their anti-protozoal activities against
,
, and
. Some of the 2,5-DKPs have shown promising activities against the target protozoans, with inhibitory concentrations (IC
) ranging from 5.4 to 9.5 µg/mL. The most active compounds also show low cytotoxicity (CC
), affording selectivity indices ≥ 15. Results allowed for observing a clear relationship between the substitution pattern at the aromatic rings of the 2,5-DKPs and their corresponding anti-
activity. Finally, calculated drug-like properties of the compounds revealed points for further structure optimization of promising drug candidates.
The Duffy binding protein of Plasmodium vivax (DBP) is a critical adhesion ligand that participates in merozoite invasion of human Duffy-positive erythrocytes. A small outbreak of P. vivax malaria, ...in a village located in a non-malarious area of Brazil, offered us an opportunity to investigate the DBP immune responses among individuals who had their first and brief exposure to malaria. Thirty-three individuals participated in the five cross-sectional surveys, 15 with confirmed P. vivax infection while residing in the outbreak area (cases) and 18 who had not experienced malaria (non-cases). In the present study, we found that only 20% (three of 15) of the individuals who experienced their first P. vivax infection developed an antibody response to DBP; a secondary boosting can be achieved with a recurrent P. vivax infection. DNA sequences from primary/recurrent P. vivax samples identified a single dbp allele among the samples from the outbreak area. To investigate inhibitory antibodies to the ligand domain of the DBP (cysteine-rich region II, DBPII), we performed in vitro assays with mammalian cells expressing DBPII sequences which were homologous or not to those from the outbreak isolate. In non-immune individuals, the results of a 12-month follow-up period provided evidence that naturally acquired inhibitory antibodies to DBPII are short-lived and biased towards a specific allele.
The rapid spread of drug resistant malaria parasites has necessitated the search for novel antimalarials and chemosensitizers capable of reversing drug resistance in the parasites. A number of ...studies have revealed the resistance reversal activities of pregnane glycosides and the antimalarial activity of a pregnane glycoside obtained from Gongronema species. However, the pregnane (2) and pregnane glycosides (1, 3–4) isolated from Gongronema latifolium leaf have not been evaluated for these activities. This study was therefore carried out to evaluate the antiplasmodial and chloroquine resistance reversal activities of a pregnane and three pregnane glycosides isolated from G. latifolium leaf in vitro. The compounds were evaluated for their inhibitory activities against P. falciparum 3D7 (a chloroquine-sensitive strain) and P. falciparum W2 (a chloroquine-resistant clone) in vitro. The activities of chloroquine in separate combination with each of the compounds against P. falciparum W2 were also evaluated. Moreover, the interaction of the active compounds (1 and 4) with selected P. falciparum proteins (PfProteins) were evaluated in silico. The results revealed that only 1 and 4 were active against P. falciparum 3D7 and P. falciparum W2. Also, 2 and 3 did not exhibit chloroquine resistance reversal activity. Activity of chloroquine against P. falciparum W2 was potentiated by 1 by 3200% at concentrations higher than 0.625 µg/mL. Also, 1 and 4 demonstrated similar binding patterns and higher binding tendencies to the selected PfProteins compared to chloroquine. Thus, 1 (iloneoside) is an antimalarial pregnane glycoside which can potentiate the activity of chloroquine against multidrug resistant P. falciparum.
•A pegnane (2) and pregnane glycosides (1, 3–4) were evaluated for their chloroquine resistance reversal activities.•Compounds 1 and 4 were found to be active against Plasmodium falciparum W2 in vitro while compounds 2 and 3 were not.•Compounds 2 and 3 did not exhibit chloroquine resistance reversal activity against Plasmodium falciparum W2 in vitro.•Compounds 1 and 4 potentiated the activity of chloroquine against chloroquine-resistant P. falciparum W2.•Parasite proteins studied exhibited higher affinities for compounds 1 and 4 compared to chloroquine, except PfPI4K.
Malaria remains one of the most serious global infectious diseases. An important target for antimalarial chemotherapy is the enzyme dihydroorotate dehydrogenase from Plasmodium falciparum (PfDHODH), ...which is responsible for the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthetic pathway. In this study, we have designed and synthesized fifteen 7-arylpyrazolo1,5-apyrimidine derivatives using ring bioisosteric replacement and molecular hybridization of functional groups based on the highly active 5-methyl-N-(naphthalen-2-yl)-2-(trifluoromethyl)- 1,2,4triazolo1,5-apyrimidin-7-amine. The compounds were tested against Plasmodium falciparum, as antimalarials in mice with P. berghei, and as inhibitors of PfDHODH. Thirteen compounds were found to be active against P. falciparum, with IC50 values ranging from 1.2 ± 0.3 to 92 ± 26 μM in the anti-HRP2 and hypoxanthine assays. Four compounds showed the highest selective index (SI), which is a ratio between cytotoxicity and activity in vitro. The inhibition of PfDHODH showed that compound 30 (R2 = CH3; R5 = CF3; Ar = 7-β-naphthyl) displayed higher and selective inhibitory activity, with IC50 = 0.16 ± 0.01 μM, followed by 25 (R2 = CH3; R5 = CH3; Ar = 7-β-Naphthyl) and 19 (R2 = CF3; R5 = CF3; Ar = 7-β-naphthyl), with IC50 = 4 ± 1 μM and 6 ± 1 μM, respectively. The trifluoromethyl group at the 2- or 5-positions of the pyrazolo1,5-apyrimidine ring led to increased drug activity. The docking results agreed with the values obtained from enzymatic assays.
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•7-arylpyrazolo1,5-apyrimidines were designed and synthesized as antiplasmodial.•Compounds were tested against P. falciparum as antimalarial and as PfDHODH inhibitors.•In P. falciparum the IC50 values have been from 1.2 to 88.2 μM.•Parasitemia in P. berghei was reduced by 50% on the 5th day inoculation.•The docking results agreed with the values obtained from enzymatic assays.
In this study, we accessed culturable fungal assemblages present in the sediments of three lakes potentially impacted anthropogenically in the Fildes Peninsula, King George Island, Antarctica and ...identified 63 taxa.
Cladosporium
sp. 2,
Pseudeurotium hygrophilum
, and
Pseudogymnoascus verrucosus
were recovered from the sampled sediments of all lakes. High concentrations of metals and the lowest fungal diversity indices were detected in the sediments of the Central Lake, which can be influenced by human activities due to their proximity to research stations to those of the other two lakes, which were far from the Antarctic stations. At least one type of biological activity was demonstrated by 40 fungal extracts. Among these,
P. hygrophilum
,
P. verrucosus
,
Penicillium glabrum
, and
Penicillium solitum
demonstrated strong trypanocidal, herbicidal, and antifungal activities. Our results suggest that an increase of the anthropogenic activities in the region might have affected the microbial diversity and composition. In addition, the fungal diversity in these lakes may be a useful model to study the effect of anthropogenic activities in Antarctica. We isolated a diverse group of fungal taxa from Antarctic lake sediments, which have the potential to produce novel compounds for the both the medical and agriculture sectors.
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