scholarly journals Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites - Trichuris muris, Brugia malayi, Heligmosomoides polygyrus and Schistosoma mansoni

2020 ◽  
Author(s):  
Frederick A Partridge ◽  
Carole JR Bataille ◽  
Ruth Forman ◽  
Amy E Marriott ◽  
Josephine Forde-Thomas ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Ex Vivo ◽  
Anthelmintic Activity ◽  
Brugia Malayi ◽  
Systematic Investigation ◽  
Parasitic Nematodes ◽  
Trichuris Muris ◽  
Heligmosomoides Polygyrus ◽  
Cure Rates ◽  
Relationship Of

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.

scholarly journals Non-sedating benzodiazepines cause contractile paralysis and tissue damage in the parasitic blood fluke Schistosoma mansoni

2019 ◽  
Author(s):  
Paul McCusker ◽  
Yeunus Mian ◽  
Guanguan Li ◽  
Michael D. Olp ◽  
V. V. N. Phani Babu Tiruveedhula ◽  
...  
Keyword(s):  
Side Effects ◽  
Schistosoma Mansoni ◽  
Anion Channels ◽  
Urinary Schistosomiasis ◽  
Starting Point ◽  
Parasitic Flatworm ◽  
Cure Rates ◽  
Trematode Infections ◽  
Relationship Of

AbstractParasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports of cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines, given the known anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970’s but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ’s anti-parasitic target is likely distinct from the human receptors that drive sedation. Therefore, we screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of imidazobenzodiazepines that immobilize worms in vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, causing extensive vacuole formation beneath the apical membrane. The imidazobenzodiazepine compound series identified has a dramatically lower (∼1 log) affinity for human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects.Author SummaryOver 200 million people are infected with schistosomiasis, yet there are limited therapeutic options available to treat this disease. The benzodiazepine meclonazepam is known to cure both intestinal and urinary schistosomiasis in animal and human studies, but dose-limiting sedation has been a barrier to its development. Little is known about the structure-activity relationship of meclonazepam and other benzodiazepines on schistosomes, or the identity of the parasite receptor for these compounds. However, schistosomes lack obvious homologs to the human GABAARs that cause sedation. This indicates that the parasite target of this drug is distinct from the host receptors that underpin dose-limiting side effects of meclonazepam, and raises the possibility that benzodiazepines with poor GABAAR affinity may still retain anti-parasitic effects. Here, we report an in vitro screen of various benzodiazepines against schistosomes, and the identification of hit compounds that are active against worms yet possess reduced affinity for the human GABAARs that cause sedation.

scholarly journals Compounds Derived from the Bhutanese Daisy, Ajania nubigena, Demonstrate Dual Anthelmintic Activity against Schistosoma mansoni and Trichuris muris

2016 ◽  
Vol 10 (8) ◽  
pp. e0004908 ◽  
Author(s):  
Phurpa Wangchuk ◽  
Mark S. Pearson ◽  
Paul R. Giacomin ◽  
Luke Becker ◽  
Javier Sotillo ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Anthelmintic Activity ◽  
Trichuris Muris

scholarly journals Anthelmintic Activity and Cytotoxic Effects of Compounds Isolated from the Fruits of Ozoroa insignis Del. (Anacardiaceae)

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1893
Author(s):  
Mthandazo Dube ◽  
Mohamad Saoud ◽  
Robert Rennert ◽  
Ghislain Wabo Fotso ◽  
Kerstin Andrae-Marobela ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Cell Lines ◽  
Antiproliferative Activity ◽  
Anthelmintic Activity ◽  
Heligmosomoides Polygyrus ◽  
Cytotoxic Effects ◽  
Ic50 Value ◽  
Hookworm Infections ◽  
Newly Transformed Schistosomula ◽  
Ht 29

Ozoroa insignis Del. is an ethnobotanical plant widely used in traditional medicine for various ailments, including schistosomiasis, tapeworm, and hookworm infections. From the so far not investigated fruits of Ozoroa insignis, the anthelmintic principles could be isolated through bioassay-guided isolation using Caenorhabditis elegans and identified by NMR spectroscopic analysis and mass spectrometric studies. Isolated 6-[8(Z)-pentadecenyl] anacardic (1), 6-[10(Z)-heptadecenyl] anacardic acid (2), and 3-[7(Z)-pentadecenyl] phenol (3) were evaluated against the 5 parasitic organisms Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum, which mainly infect humans and other mammals. Compounds 1–3 showed good activity against Schistosoma mansoni, with compound 1 showing the best activity against newly transformed schistosomula with 50% activity at 1µM. The isolated compounds were also evaluated for their cytotoxic properties against PC-3 (human prostate adenocarcinoma) and HT-29 (human colorectal adenocarcinoma) cell lines, whereby compounds 2 and 3 showed antiproliferative activity in both cancer cell lines, while compound 1 exhibited antiproliferative activity only on PC-3 cells. With an IC50 value of 43.2 µM, compound 3 was found to be the most active of the 3 investigated compounds.

scholarly journals Benzimidazole and Aminoalcohol Derivatives Show in Vitro Anthelmintic Activity Against Trichuris Muris and Heligmosomoides Polygyrus

2022 ◽  
Author(s):  
Elora Valderas-García ◽  
Cécile Häberli ◽  
María Álvarez Bardón ◽  
Nerea Escala ◽  
Verónica Castilla Gómez de Agüero ◽  
...  
Keyword(s):  
Adult Stage ◽  
Anthelmintic Activity ◽  
Gastrointestinal Nematodes ◽  
Economic Losses ◽  
Parasitic Infections ◽  
Trichuris Muris ◽  
Heligmosomoides Polygyrus ◽  
Derivatives Of

Abstract Background: Infections by gastrointestinal nematodes cause significant economic losses and disease in both human and animals worldwide. The discovery of novel anthelmintic drugs is a crucial point in maintaining control of these parasitic infections.Methods: For this purpose, the aim of the present study was to evaluate the potential anthelmintic activity of three series of compounds against the gastrointestinal nematodes Trichuris muris and Heligmosomoides polygyrusin vitro. The compounds tested are derivatives of benzimidazole, lipidic aminoalcohols and diamines. A primary screening was performed to select those compounds with an ability to inhibit T. muris L1 motility by more than 90% at a single concentration of 100 µM, and then, their respective IC50s were calculated. Those compounds with IC50 lower than 10 µM were also tested against the adult stage of T. muris and H. polygyrus at a single concentration of 10µM.Results: Of the 41 initial compounds screened, only compounds AO14, BZ6 and BZ12 had IC50s lower than 10 µM on T. muris L1 assay, showing IC50 values of 3.30, 8.89 and 4.17 µM, respectively. However, only two of them displayed activity against the adult stage of the parasites: BZ12 killed 81% of adults of T. muris (IC50 of 8.1 µM) and 53% of H. polygyrus while BZ6 killed 100% of H. polygyrus adults (IC50 of 5.3 µM) but only 17% of T. muris. Conclusions: BZ6 and BZ12 could be considered as potential candidates for further in vivo efficacy testing.

scholarly journals Ovarian Accumulation of Nanoemulsions: Impact of Mice Age and Particle Size

2021 ◽  
Vol 22 (15) ◽  
pp. 8283
Author(s):  
Eike Folker Busmann ◽  
Julia Kollan ◽  
Karsten Mäder ◽  
Henrike Lucas
Keyword(s):  
Particle Size ◽  
Ex Vivo ◽  
Reticuloendothelial System ◽  
Systematic Investigation ◽  
Measured Signal ◽  
Reproductive Aging ◽  
Sex Steroid Hormone ◽  
Adult Mice ◽  
Radiant Efficiency

Nanotechnology in the field of drug delivery comes with great benefits due to the unique physicochemical properties of newly developed nanocarriers. However, they may come as well with severe toxicological side effects because of unwanted accumulation in organs outside of their targeted site of actions. Several studies showed an unintended accumulation of various nanocarriers in female sex organs, especially in the ovaries. Some led to inflammation, fibrosis, or decreasing follicle numbers. However, none of these studies investigated ovarian accumulation in context to both reproductive aging and particle size. Besides the influences of particle size, the biodistribution profile may be altered as well by reproductive aging because of reduced capacities of the reticuloendothelial system (RES), changes in sex steroid hormone levels as well as altering ovarian stromal blood flow. This systematic investigation of the biodistribution of intravenously (i.v) injected nanoemulsions revealed significant dependencies on the two parameters particle size and age starting from juvenile prepubescent to senescent mice. Using fluorescent in vivo and ex vivo imaging, prepubescent mice showed nearly no accumulation of nanoemulsion in their uteri and ovaries, but high accumulations in the organs of the RES liver and spleen independently of the particle size. In fertile adult mice, the accumulation increased significantly in the ovaries with an increased particle size of the nanoemulsions by nearly doubling the portion of the average radiant efficiency (PARE) to ~10% of the total measured signal of all excised organs. With reproductive aging and hence loss of fertility in senescent mice, the accumulation decreased again to moderate levels, again independently of the particle size. In conclusion, the ovarian accumulation of these nanocarriers depended on both the age plus the particle size during maturity.

The relationship between the age of Schistosoma mansoni cercariae and their ability to penetrate and infect the mammalian host

Parasitology ◽  
1983 ◽  
Vol 87 (3) ◽  
pp. 481-492 ◽  
Author(s):  
J. Ruth Lawson ◽  
R. A. Wilson
Keyword(s):  
Schistosoma Mansoni ◽  
Stratum Corneum ◽  
Mass Mortality ◽  
Mammalian Host ◽  
Energy Reserves ◽  
Age Related ◽  
Abdominal Route ◽  
Relationship Of ◽  
The Relationship ◽  
Related Mortality

SummaryThe ability of the cercariae of Schistosoma mansoni to penetrate the tails of mice was shown to remain constant throughout their lives. However, their capacity to establish themselves and then reach maturity decreased as they aged. The abdominal route of penetration produced consistently higher maturation rates than the tail route. Significantly different maturation rates were obtained by modifying the standard tail infection technique. Evidence is presented that age-related mortality of schisto-somula occurs within 24 h of penetration and may be associated with the exhaustion of energy reserves during the penetration of the stratum corneum. The relationship of this age-related mortality to ‘mass mortality’ is discussed.

Mitochondria as a potential target for the development of prophylactic and therapeutic drugs against Schistosoma mansoni infection

2021 ◽  
Author(s):  
Keith Kiplangat Talaam ◽  
Daniel Ken Inaoka ◽  
Takeshi Hatta ◽  
Daigo Tsubokawa ◽  
Naotoshi Tsuji ◽  
...  
Keyword(s):  
Drug Development ◽  
Schistosoma Mansoni ◽  
Worm Burden ◽  
Consumption Rate ◽  
Therapeutic Agent ◽  
Ex Vivo ◽  
Prophylactic Agent ◽  
Therapeutic Drugs ◽  
Pyrvinium Pamoate

Emergence of parasites resistant to praziquantel, the only therapeutic agent, and its ineffectiveness as a prophylactic agent (inactive against the migratory/juvenile Schistosoma mansoni ), makes the development of new antischistosomal drugs urgent. The parasite’s mitochondrion is an attractive target for drug development because this organelle is essential for survival throughout the parasite’s life cycle. We investigated the effects of 116 compounds against Schistosoma mansoni cercariae motility that have been reported to affect mitochondria-related processes in other organisms. Next, eight compounds plus two controls (mefloquine and praziquantel) were selected and assayed against motility of schistosomula ( in vitro ) and adults ( ex vivo ). Prophylactic and therapeutic assays were performed using infected mouse models. Inhibition of oxygen consumption rate (OCR) was assayed using Seahorse XFe24 Analyzer. All selected compounds showed excellent prophylactic activity, reducing the worm burden in the lungs to less than 15% that obtained in the vehicle control. Notably, ascofuranone showed the highest activity with a 98% reduction of the worm burden, suggesting the potential for development of ascofuranone as a prophylactic agent. The worm burden of infected mice with S. mansoni at the adult stage was reduced by more than 50% in mice treated with mefloquine, nitazoxanide, amiodarone, ascofuranone, pyrvinium pamoate, or plumbagin. Moreover, adult mitochondrial OCR was severely inhibited by ascofuranone, atovaquone, and nitazoxanide, while pyrvinium pamoate inhibited both mitochondrial and non-mitochondrial OCRs. These results demonstrate that the mitochondria of S. mansoni are feasible target for drug development.

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