scholarly journals Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

Inorganics ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 59
Author(s):  
Oksana Desiatkina ◽  
Serena K. Johns ◽  
Nicoleta Anghel ◽  
Ghalia Boubaker ◽  
Andrew Hemphill ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Organometallic Complexes ◽  
Host Cells ◽  
Arene Complexes ◽  
Antiparasitic Activity ◽  
Human Foreskin Fibroblasts ◽  
Hybrid Molecules ◽  
Dinuclear Ruthenium ◽  
Alamarblue Assay

Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)–arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4-naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 µM, five compounds strongly impaired parasite proliferation by >90%, and HFF viability was retained at 50% or more, and they were further subjected to T. gondii β-gal dose-response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC50 (half-maximal inhibitory concentration) values 0.063 and 0.152 µM, and low or intermediate impairment of HFF viability at 2.5 µM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity.

scholarly journals Conjugates Containing Two and Three Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Units as In Vitro Antiparasitic and Anticancer Agents

2020 ◽  
Vol 13 (12) ◽  
pp. 471
Author(s):  
Valentin Studer ◽  
Nicoleta Anghel ◽  
Oksana Desiatkina ◽  
Timo Felder ◽  
Ghalia Boubaker ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Alkyl Aryl ◽  
Antiparasitic Activity ◽  
Human Foreskin Fibroblasts ◽  
Adenocarcinoma Cells ◽  
Human Lung Adenocarcinoma Cells ◽  
Ic50 Values ◽  
Dinuclear Ruthenium

The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasmagondii tachyzoites constitutively expressing β-galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited T.gondii proliferation with IC50 values ranging from 90 to 539 nM, and seven derivatives displayed IC50 values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC50 values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC50 values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates 6–10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues 11–14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.

scholarly journals The ketolide antibiotics HMR 3647 and HMR 3004 are active against Toxoplasma gondii in vitro and in murine models of infection.

1997 ◽  
Vol 41 (10) ◽  
pp. 2137-2140 ◽  
Author(s):  
F G Araujo ◽  
A A Khan ◽  
T L Slifer ◽  
A Bryskier ◽  
J S Remington
Keyword(s):  
Toxoplasma Gondii ◽  
Protozoan Parasite ◽  
Host Cells ◽  
Resistant Bacteria ◽  
New Class ◽  
Human Foreskin Fibroblasts ◽  
Significant Toxicity ◽  
Different Strains

Ketolides are a new class of macrolide antibiotics that have been shown to be active against a variety of bacteria including macrolide-resistant bacteria and mycobacteria. We examined two ketolides, HMR 3647 and HMR 3004, for their in vitro and in vivo activities against the protozoan parasite Toxoplasma gondii. In vitro, both ketolides at concentrations as low as 0.05 microg/ml markedly inhibited replication of tachyzoites of the RH strain within human foreskin fibroblasts. HMR 3004 demonstrated some toxicity for host cells after they were exposed to 5 microg of the drug per ml for 72 h. In contrast, HMR 3647 did not show any significant toxicity even at concentrations as high as 25 microg/ml. In vivo, both ketolides provided remarkable protection against death in mice lethally infected intraperitoneally with tachyzoites of the RH strain or orally with tissue cysts of the C56 strain of T. gondii. A dosage of 100 mg of HMR 3647 per kg of body weight per day administered for 10 days protected 50% of mice infected with tachyzoites. The same dosage of HMR 3004 protected 100% of the mice. In mice infected with cysts, a dosage of 30 mg of HMR 3647 per kg per day protected 100% of the mice, whereas a dosage of 40 mg of HMR 3004 per kg per day protected 75% of the mice. These results demonstrate that HMR 3647 and HMR 3004 possess excellent activities against two different strains of T. gondii and may be useful for the treatment of toxoplasmosis in humans.

scholarly journals Comparative Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii in vitro and in Pregnant Mice Infected with T. gondii Oocysts

2021 ◽  
Author(s):  
Jessica Ramseier ◽  
Dennis Imhof ◽  
Nicoleta Anghel ◽  
Kai Hänggeli ◽  
Richard Betteck ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Vertical Transmission ◽  
Oral Treatment ◽  
Parasite Burden ◽  
Host Cells ◽  
Parasitic Infections ◽  
Human Foreskin Fibroblasts ◽  
Half Maximal Effective Concentration ◽  
Pregnant Mice

The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacte-rial and parasitic infections, most notably coccidiosis in poultry and in ruminants. We have in-vestigated the effects of treatment of Toxoplasma gondii in infected human foreskin fibroblasts (HFF) with DCQ. It induced distinct alterations in the parasite mitochondrion within 24h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC50) of 1.1 nM and the high selec-tivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with T. gondii oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than T. gondii infection alone, and did not prevent vertical transmission. Thus, three quinoline-O-carbamate derivatives of DCQ antici-pated to have better physicochemical properties than DCQ were assessed in vitro. One such com-pound RMB060 displayed an exceedingly low IC50 of 0.07 nM when applied concomitantly with infection of host cells and had no impact on HFF viability at 10 µM. As was the case for DCQ, RMB060 treatment resulted in alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6h after commencement of treatment. After 48h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features remi-niscent of bradyzoites. Exposure of infected cultures to 300 nM RMB060 for 52 days did not re-sult in complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. Treatment of mice infected with T. gondii oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.

scholarly journals Targeting Streptococcus pneumoniae UDP-glucose pyrophosphorylase (UGPase): in vitro validation of a putative inhibitor

2020 ◽  
Vol 14 (1) ◽  
pp. 26-33
Author(s):  
Monica Sharma ◽  
Swati Sharma ◽  
Pallab Ray ◽  
Anuradha Chakraborti
Keyword(s):  
Streptococcus Pneumoniae ◽  
Capsular Polysaccharide ◽  
Inhibitory Concentration ◽  
A549 Cells ◽  
Host Cells ◽  
Genome Plasticity ◽  
Leloir Pathway ◽  
Tnf Α ◽  
Respiratory Epithelial

Background: Genome plasticity of Streptococcus pneumoniae is responsible for the reduced efficacy of various antibiotics and capsular polysaccharide based vaccines. Therefore targets independent of capsular types are sought to control the pneumococcal pathogenicity. UcrDP-glucose pyrophosphorylase (UGPase) is one such desired candidate being responsible for the synthesis of UDP-glucose, a sugar-precursor in capsular biosynthesis and metabolic Leloir pathway. Being crucial to pneumococcal pathobiology, the effect of UGPase inhibition on virulence was evaluated in vitro. Methods: A putative inhibitor (UDP) was evaluated for effective inhibitory concentration in S. pneumoniae and A549 cells, its efficacy and toxicity. Effect of UDP on adherence and phagocytosis was measured in human respiratory epithelial (A549 and HEp-2) and macrophage (THP1 and J774.A.1) cell lines respectively. Results: A differential effective inhibitory concentration of UDP for UGPase inhibition was observed in S. pneumoniae and A549 cells i.e. 5 µM and 100 µM respectively. UDP treatments lowered percent cytotoxicity in pneumococcal infected monolayers and didn't exert adverse effects on viabilities. S. pneumoniae adherence to host cells was decreased significantly with UDP treatments. UDP induced the secretion of IL-1β, TNF-α, IL-6, and IL-8 and increased pneumococcal phagocytosis. Conclusion: Our study shows UDP mediated decrease in the virulence of S. pneumoniae and demonstrates UDP as an effective inhibitor of pneumococcal UGPase.

scholarly journals Ceftazidime Is a Potential Drug to Inhibit SARS-CoV-2 Infection In Vitro by Blocking Spike Protein-ACE2 Interaction

2020 ◽  
Author(s):  
ChangDong Lin ◽  
Yue Li ◽  
MengYa Yuan ◽  
MengWen Huang ◽  
Cui Liu ◽  
...  
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Inhibitory Concentration ◽  
Cell Entry ◽  
Host Cells ◽  
First Line ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

SUMMARYCoronavirus Disease 2019 (COVID-19) spreads globally as a sever pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cell entry of SARS-CoV-2 mainly depends on binding of the viral spike (S) proteins to angiotensin converting enzyme 2 (ACE2) on host cells. Therefore, repurposing of known drugs to inhibit S protein-ACE2 interaction could be a quick way to develop effective therapy for COVID-19. Using a high-throughput screening system to investigate the interaction between spike receptor binding domain (S-RBD) and ACE2 extracellular domain, we screened 3581 FDA-approved drugs and natural small molecules and identified ceftazidime as a potent compound to inhibit S-RBD–ACE2 interaction by binding to S-RBD. In addition to significantly inhibit S-RBD binding to HPAEpiC cells, ceftazidime efficiently prevented SARS-CoV-2 pseudovirus to infect ACE2-expressing 293T cells. The inhibitory concentration (IC50) was 113.2 μM, which is far below the blood concentration (over 300 μM) of ceftazidime in patients when clinically treated with recommended dose. Notably, ceftazidime is a drug clinically used for the treatment of pneumonia with minimal side effects compared with other antiviral drugs. Thus, ceftazidime has both anti-bacterial and anti-SARS-CoV-2 effects, which should be the first-line antibiotics used for the clinical treatment of COVID-19.

scholarly journals Trioxaquines Are New Antimalarial Agents Active on All Erythrocytic Forms, Including Gametocytes

2007 ◽  
Vol 51 (4) ◽  
pp. 1463-1472 ◽  
Author(s):  
Françoise Benoit-Vical ◽  
Joël Lelièvre ◽  
Antoine Berry ◽  
Caroline Deymier ◽  
Odile Dechy-Cabaret ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Mice Model ◽  
Additional Advantage ◽  
Antimalarial Agents ◽  
Hybrid Molecules ◽  
Resistant Strains ◽  
Antimalarial Chemotherapy

ABSTRACT Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.

scholarly journals Synthesis, Characterization and Antiparasitic Activity of Organometallic Derivatives of the Anthelmintic Drug Albendazole

2020 ◽  
Author(s):  
Yan Lin ◽  
Yih Ching Ong ◽  
Sarah Keller ◽  
Johannes Karges ◽  
Rafika Bouchene ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
Organometallic Compounds ◽  
Host Cells ◽  
World Health ◽  
Full Potential ◽  
Trichuris Muris ◽  
Antiparasitic Activity ◽  
Derivatives Of

Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Albendazole (ABZ) is a broad‐spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with the organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths but also protozoans, namely Trichuris muris adult, Heligmosomoides polygygrus adult, Schistosoma mansoni adult, Giardia lamblia, Haemonchus contortus xL3s and Toxoplasma gondii to determine the full potential of our new compounds. Worthy of note, the ferrocene‐containing ABZ analogue 2d exhibited over 70% activity against T. muris adult in vitro and no toxicity to mammalian cells up to 100 µM. Against T. gondii, the ferrocene‐containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. However, the activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro could rather be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg/kg dose, the compounds showed moderate worm burden reductions and low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.<br>

scholarly journals Synthesis, Characterization and Antiparasitic Activity of Organometallic Derivatives of the Anthelmintic Drug Albendazole

2020 ◽  
Author(s):  
Yan Lin ◽  
Yih Ching Ong ◽  
Sarah Keller ◽  
Johannes Karges ◽  
Rafika Bouchene ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
Organometallic Compounds ◽  
Host Cells ◽  
World Health ◽  
Full Potential ◽  
Trichuris Muris ◽  
Antiparasitic Activity ◽  
Derivatives Of

Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Albendazole (ABZ) is a broad‐spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with the organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths but also protozoans, namely Trichuris muris adult, Heligmosomoides polygygrus adult, Schistosoma mansoni adult, Giardia lamblia, Haemonchus contortus xL3s and Toxoplasma gondii to determine the full potential of our new compounds. Worthy of note, the ferrocene‐containing ABZ analogue 2d exhibited over 70% activity against T. muris adult in vitro and no toxicity to mammalian cells up to 100 µM. Against T. gondii, the ferrocene‐containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. However, the activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro could rather be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg/kg dose, the compounds showed moderate worm burden reductions and low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.<br>

scholarly journals A Novel Benzodioxole-Containing Inhibitor of Toxoplasma gondii Growth Alters the Parasite Cell Cycle

2011 ◽  
Vol 55 (12) ◽  
pp. 5438-5451 ◽  
Author(s):  
Edwin Kamau ◽  
Tracy Meehan ◽  
Mark D. Lavine ◽  
Gustavo Arrizabalaga ◽  
Gabriela Mustata Wilson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Toxoplasma Gondii ◽  
Host Cells ◽  
Antiparasitic Activity ◽  
Content Type ◽  
M Phase ◽  
The Individual ◽  
Microarray Analyses ◽  
Novel Scaffold

ABSTRACTToxoplasma gondiiis an obligate intracellular parasite that can cause disease in the developing fetus and in immunocompromised humans. Infections can last for the life of the individual, and to date there are no drugs that eliminate the chronic cyst stages that are characteristic of this parasite. In an effort to identify new chemical scaffolds that could form the basis for new therapeutics, we carried out a chemoinformatic screen for compounds that had the potential to interact with members of a superfamily of parasite-secreted kinases and assayed them for growth inhibitionin vitro. Of 17 candidate compounds, we identified one with potent antiparasitic activity. The compound has a 50% inhibitory concentration (IC50) of ∼2 nM, and structure-function analyses implicate the benzodioxole moiety in its action. The compound does not appear to be cytotoxic to host cells. Using microarray analyses of both parasites and host cells treated with the compound, we found that the levels of very few host cell transcripts are altered by the compound, while a large number of parasite transcripts have a different abundance after compound treatment. Gene ontology analyses of parasite transcripts with a different abundance revealed an enrichment of cell cycle-related genes, suggesting that the compound alters progression of the parasite through the cell cycle. Assaying the nuclear content of treated parasites demonstrated that compound treatment significantly increased the percentage of parasites in the S/M phase of the cell cycle compared to controls. This compound and its analogs represent a novel scaffold with antiparasitic activity.

scholarly journals N-Cinnamoylated Aminoquinolines as Promising Antileishmanial Agents

2013 ◽  
Vol 57 (10) ◽  
pp. 5112-5115 ◽  
Author(s):  
S. Vale-Costa ◽  
J. Costa-Gouveia ◽  
B. Pérez ◽  
T. Silva ◽  
C. Teixeira ◽  
...  
Keyword(s):  
High Activity ◽  
Cinnamic Acid ◽  
Leishmania Infantum ◽  
Inhibitory Concentration ◽  
Host Cells ◽  
Content Type ◽  
Low Toxicity ◽  
Antileishmanial Activities ◽  
Modest Activity

ABSTRACTA series of cinnamic acid conjugates of primaquine and chloroquine were evaluated for theirin vitroantileishmanial activities. Although primaquine derivatives had modest activity, chloroquine conjugates exhibited potent activity against both promastigotes (50% inhibitory concentration [IC50] = 2.6 to 21.8 μM) and intramacrophagic amastigotes (IC50= 1.2 to 9.3 μM) ofLeishmania infantum. Both the high activity of these chloroquine analogues and their mild-to-low toxicity toward host cells make them promising leads for the discovery of new antileishmanial agents.

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