Marine halophytes are an outstanding reservoir of natural products and several species have anti-infectious traditional uses. However, reports about their potential use against neglected tropical ...ailments, such as Chagas disease, are scarce. This work evaluated for the first time the in vitro anti-Trypanosoma cruzi activity of extracts from the aromatic and medicinal species Helichrysum italicum subsp. picardii (Boiss. & Reut.) Franco (Asteraceae, everlasting) and Crithmum maritimum L. (Apiaceae, sea fennel). For that purpose, decoctions, tinctures, and essential oils from everlasting’s flowers and sea fennel’s stems, leaves, and flowers were tested against intracellular amastigotes of two T. cruzi strains. The extract from the sea fennel flower decoction displayed significant anti-trypanosomal activity and no toxicity towards the host cell (EC50 = 17.7 µg/mL, selectivity index > 5.65). Subsequent fractionation of this extract afforded 5 fractions that were re-tested in the same model of anti-parasitic activity. Fraction 1 was the most active and selective (EC50 = 0.47 μg/mL, selectivity index = 59.6) and was submitted to preparative thin-layer chromatography. One major compound was identified, falcarindiol, which was likely the one responsible for the observed anti-trypanosomal activity. This was confirmed using a commercially sourced molecule. Target-fishing studies showed falcarindiol as a ligand of T. cruzi spermidine synthase, pointing to a potential enzyme-inhibiting anti-trypanosomal mechanism of action. Overall, this work shows that sea fennel can provide effective anti-parasitic molecule(s) with potential pharmacological applications in the treatment of CD.
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The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the ...corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a ...published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Brazil concentrates the largest number of primate species in the world. In the present study, an extensive literature review of ticks on New World wild monkeys has been carried out, demonstrating ...that between the years 1912 to 2018, 182 larvae, 137 nymphs and 31 adult ticks (10 males and 21 females) were collected on 78 primates (from 12 different species) in 28 distinct localities in the Brazilian territory. Additionally, examination of allotments of 11 tick collections of Brazil revealed that from 1919 to 2019, 93 larvae, 91 nymphs and 175 adult ticks (62 males and 113 females) were collected from 100 monkeys (among 20 different species) from 43 localities in distinct Brazilian biomes. Overall, 19 tick species were identified on wild primates in the country: Amblyomma aureolatum (Pallas, 1772), Amblyomma cajennense (Fabricius, 1787) sensu stricto, Amblyomma coelebs Neumann, 1899, Amblyomma dubitatum Neumann, 1899, Amblyomma geayi Neumann, 1899, Amblyomma incisum Neumann, 1906, Amblyomma longirostre (Koch, 1844), Amblyomma naponense (Packard, 1869), Amblyomma nodosum Neumann, 1899, Amblyomma ovale Koch, 1844, Amblyomma parkeri Fonseca & Aragão, 1952, Amblyomma romarioi Martins, Luz & Labruna, 2019, Amblyomma rotundatum Koch, 1844, Amblyomma sculptum Berlese, 1888, Haemaphysalis juxtakochi Cooley, 1946, Ixodes fuscipes Koch, 1844, Rhipicephalus microplus (Canestrini, 1888), Rhipicephalus sanguineus (Latreille, 1806) sensu lato,and Ornithodoros rostratus Aragão, 1911. The presence of A. incisum, A. naponense, A. nodosum, A. rotundatum and I. fuscipes on monkeys is recorded for the first time. Thisresearch is therefore a significant contribution to the knowledge of tick speciesassociated with non-human primates in the Neotropical region.
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BFBNIB, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Amblyomma ticks are vectors of both Rickettsia rickettsii and R. parkeri in the Americas, where capybaras (Hydrochoerus hydrochaeris) are the main hosts in urban areas, thus contributing to the ...transmission of spotted fever. Herein, we studied: (i) the seasonal dynamics and abundance of ticks in areas where capybaras live, (ii) the effect of environmental variables on tick abundance, and (iii) the presence of Rickettsia-infected ticks. Between September 2021 and September 2022, we sampled ticks using cloth-dragging at 194 sites on the shore of Lake Paranoá in Brasília, Brazil. We measured environmental data (season, vegetation type, canopy density, temperature, humidity, and presence or vestige of capybara) at each site. Nymphs and adults were morphologically identified to the species level, and a selected tick sample including larvae was subjected to genotypic identification. We investigated Rickettsia-infected ticks by PCR (gltA, htrA, ompB, and ompA genes) and associations between tick abundance and environmental variables using Generalized Linear Models. A total of 30,334 ticks (96% larvae) were captured. Ticks were identified as Amblyomma, with A. sculptum comprising 97% of the adult/nymphs. Genotype identification of a larval sample confirmed that 95% belonged to A. dubitatum. Seasonal variables showed significant effects on tick abundance. Most larvae and nymphs were captured during the early dry season, while the adults were more abundant during the wet season. Vegetation variables and the presence of capybaras showed no association with tick abundance. Rickettsia parkeri group and R. bellii were identified in A. dubitatum, while A. sculptum presented R. bellii. We conclude that: (i) Amblyomma ticks are widely distributed in Lake Paranoá throughout the year, especially larvae at the dry season, (ii) the abundance of Amblyomma ticks is explained more by climatic factors than by vegetation or presence of capybaras, and (iii) A. dubitatum ticks are potential vectors of R. parkeri in Brasília.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND: Despite the ongoing trend towards centralized procurement for Medical Devices (MDs) in Italy, the lack of national guidelines translates into heterogeneity of tender specifications and ...lack of comparability and governability of MDs purchasing processes. OBJECTIVES: To develop a methodology for comparative analysis of tenders for MDs procurement, with the ultimate goal of drafting a national standardized tender dossier. METHODS: The work focused on sanitary gloves. We performed a systematic search and collected documents related to all awarded, expired and ongoing Italian regional tenders from 2015 onwards. We developed an ad hoc extraction protocol of relevant information and performed comprehensive analyses at both dossier and lot level. RESULTS: 13 regional tenders were implemented in 12 out of the 21 Italian Regions during the analyzed period. Both structure and contents of the retrieved documents were highly heterogeneous among the contracting authorities. The characteristics used in lot description were more detailed than those included in the Italian National Classification System of MDs (CND). Consequently, the groups of MDs in the CND include heterogeneous devices. This should be considered in comparative analysis of MDs unit price. Finally, awarding criteria of lots differed substantially among tenders, with quality weighting varying between 30 and 60%. CONCLUSIONS: Tender specifications and criteria should be harmonized among contracting authorities. A higher adherence between classification system and characteristics of the purchased goods is recommended. Finally, technical aspects and quality should have a higher importance in awarding public contracts. Our analysis contributed to the implementation of the procurement of MDs in Italy in several ways. First, the Italian Ministry of Health (MoH) has started a revision of the CND. Second, the authors supported the Italian MoH and Regions in drafting national guidelines for procurement of MDs and a standardized tender dossier for sanitary gloves, aimed at overcoming the current fragmentation in public procurement documents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The compound 3a,10b-dihydro-1H-cyclopentabnaphtho2,3-dfuran-5,10-dione (IVS320) is a naphthoquinone with antifungal and antichagasic potential, which however has low aqueous solubility. To increase ...bioavailability, inclusion complexes with β-cyclodextrin (βCD) and methyl-β-cyclodextrin (MβCD) were prepared by physical mixture (PM), kneading (KN) and rotary evaporation (RE), and their in vitro anti-SARS-CoV-2 and antichagasic potential was assessed. The formation of inclusion complexes led to a change in the physicochemical characteristics compared to IVS320 alone as well as a decrease in crystallinity degree that reached 74.44% for the IVS320-MβCD one prepared by RE. The IVS320 and IVS320-MβCD/RE system exhibited anti-SARS-CoV-2 activity, showing half maximal effective concentrations (EC50) of 0.47 and 1.22 μg/mL, respectively. Molecular docking simulation suggested IVS320 ability to interact with the SARS-CoV-2 viral protein. Finally, the highest antichagasic activity, expressed as percentage of Tripanosoma cruzi growth inhibition, was observed with IVS320-βCD/KN (70%) and IVS320-MβCD/PM (72%), while IVS320 alone exhibited only approximately 48% inhibition at the highest concentration (100 μg/mL).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Hence, peptidomimetic cruzipain inhibitors having a reactive ...group (known as warhead) are subject to continuous studies to discover novel antichagasic compounds. Here, we evaluated how different warheads for a set of structurally similar related compounds could inhibit the activity of cruzipain and, ultimately, their trypanocidal effect. We first investigated
in silico
the intrinsic reactivity of these compounds by applying the Fukui index to correlate it with the enzymatic affinity. Then, we evaluated their potency against
T. cruzi
(Y and Tulahuen strains), which revealed the reversible cruzain inhibitor
Neq0656
as a better trypanocidal agent (EC
Y.strain
50
= 0.1 μM; SI = 58.4) than the current drug benznidazole (EC
Y.strain
50
= 5.1 μM; SI > 19.6). We also measured the half-life time by HPLC analysis of three lead compounds in the presence of glutathione and cysteine to experimentally assess their intrinsic reactivity. Results clearly illustrated the reactivity trend for the warheads (azanitrile > aldehyde > nitrile), where the aldehyde displayed an intermediate intrinsic reactivity. Therefore, the aldehyde bearing peptidomimetic compounds should be subject for in-depth evaluation in the drug discovery process.
Aldehyde peptide like compounds display a bivalent reactive profile and improved antichagasic potency.
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