Abstract:Pharmacophore hybridization has recently been employed in the search for antimalarial lead compounds. This approach chemically links two pharmacophores, each with their own antimalarial activity and ideally with different modes of action, into a single hybrid molecule with the goal to improve therapeutic properties. In this paper, we report the synthesis of novel 7-chloro-4-aminoquinoline/primary sulfonamide hybrid compounds. The chlorinated 4-aminoquinoline scaffold is the core structure of chloroquine, an es… Show more
“…Compounds a-15 and a-17 were tested for toxic effects on a human neonatal foreskin fibroblast (NFF) cell line; tolfenpyrad was included as a reference control. Selectivity indices of these compounds on the motility of exsheathed third- and fourth-stage larvae (at 72 h) (xL3s and L4s) and the development of L4s (at 7 days) were calculated using a recognised formula [16]CompoundIC 50 (μM) for NFF cellsSelectivity index (SI) for H. contortus
xL3 motilityL4 motilityL4 development
a-15
66.72 ± 10.041.202.5416.81
a-17
72.15 ± 1.611.404.6321.10Tolfenpyrad> 50> 16.40> 1666.70> 625Fig. 3Respiration rates of Haemonchus contortus treated with test or control compounds in vitro.…”
Section: Resultsmentioning
confidence: 99%
“…To determine IC 50 values, the data from each assay (xL3 motility, L4 motility and development) were converted to a percentage with reference to the negative-control (LB* + 0.5% DMSO), and IC 50 values determined using a variable slope four-parameter equation, constraining the top value to 100% and using a least squares (ordinary) fit model (v.6 GraphPad Software). The toxicity of selected compounds was measured by assessing their inhibition of the proliferation of human neonatal foreskin fibroblast (NFF) cells as described previously [16]. Selectivity indices (SIs) were calculated as follows: IC 50 for NFF cells / IC 50 for H. contortus ).…”
Background:In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC 50 values ranging between~3.4 and 55.6 μM. We studied the effect of these two 'hit' compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.
“…Compounds a-15 and a-17 were tested for toxic effects on a human neonatal foreskin fibroblast (NFF) cell line; tolfenpyrad was included as a reference control. Selectivity indices of these compounds on the motility of exsheathed third- and fourth-stage larvae (at 72 h) (xL3s and L4s) and the development of L4s (at 7 days) were calculated using a recognised formula [16]CompoundIC 50 (μM) for NFF cellsSelectivity index (SI) for H. contortus
xL3 motilityL4 motilityL4 development
a-15
66.72 ± 10.041.202.5416.81
a-17
72.15 ± 1.611.404.6321.10Tolfenpyrad> 50> 16.40> 1666.70> 625Fig. 3Respiration rates of Haemonchus contortus treated with test or control compounds in vitro.…”
Section: Resultsmentioning
confidence: 99%
“…To determine IC 50 values, the data from each assay (xL3 motility, L4 motility and development) were converted to a percentage with reference to the negative-control (LB* + 0.5% DMSO), and IC 50 values determined using a variable slope four-parameter equation, constraining the top value to 100% and using a least squares (ordinary) fit model (v.6 GraphPad Software). The toxicity of selected compounds was measured by assessing their inhibition of the proliferation of human neonatal foreskin fibroblast (NFF) cells as described previously [16]. Selectivity indices (SIs) were calculated as follows: IC 50 for NFF cells / IC 50 for H. contortus ).…”
Background:In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC 50 values ranging between~3.4 and 55.6 μM. We studied the effect of these two 'hit' compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.
“…To determine IC 50 values, the data from each assay (xL3 motility, L4 motility and development) were converted to a percentage with reference to the negative-control (LB* + 0.5% DMSO), and IC 50 values determined using a variable slope four-parameter equation, constraining the top value to 100% and using a least squares (ordinary) fit model (v.6 GraphPad Software). Selectivity indices (SIs) were calculated using a recognised formula (SI = human fibroblast (MRC-5) cells IC 50 / H. contortus IC 50 ; Fisher et al., 2014) employing cytotoxicity data linked to the Pathogen Box compounds.…”
There is a substantial need to develop new medicines against parasitic diseases via public-private partnerships. Based on high throughput phenotypic screens of largely protozoal pathogens and bacteria, the Medicines for Malaria Venture (MMV) has recently assembled an open-access ‘Pathogen Box’ containing 400 well-curated chemical compounds. In the present study, we tested these compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility, growth and development of H. contortus. We also studied the effect of the ‘hit’ compound on mitochondrial function by measuring oxygen consumption. Among the 400 Pathogen Box compounds, we identified one chemical, called tolfenpyrad (compound identification code: MMV688934) that reproducibly inhibits xL3 motility as well as L4 motility, growth and development, with IC50 values ranging between 0.02 and 3 μM. An assessment of mitochondrial function showed that xL3s treated with tolfenpyrad consumed significantly less oxygen than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Given that tolfenpyrad was developed as a pesticide and has already been tested for absorption, distribution, excretion, biotransformation, toxicity and metabolism, it shows considerable promise for hit-to-lead optimisation and/or repurposing for use against H. contortus and other parasitic nematodes. Future work should assess its activity against hookworms and other pathogens that cause neglected tropical diseases.
“…Cell toxicity was assessed as described previously (42). In brief, neonatal foreskin fibroblast (NFF) cells were cultured in RPMI 1640 medium (Thermo Fisher Scientific) that was supplemented with 10% fetal calf serum (CSL Biosciences, Parkville, VIC, Australia) and 1% streptomycin (Thermo Fisher Scientific).…”
Section: Testing Of Cell Toxicity and Selectivity In Vitromentioning
As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mitoribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic () and free-living () nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity the mitochondrial respiratory chain.
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