The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Jennifer Keiser - One of the best experts on this subject based on the ideXlab platform.
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parallelized impedance based platform for continuous dose response characterization of Antischistosomal drugs
Advanced Biosystems, 2020Co-Authors: Paolo S Ravaynia, Jennifer Keiser, Flavio C Lombardo, Stefan Biendl, Matthias A Dupuch, Andreas Hierlemann, Mario M ModenaAbstract:Schistosomiasis is an acute and chronic disease caused by tropical parasitic worms of the genus Schistosoma, which parasitizes annually over 200 million people worldwide. Screening of Antischistosomal compounds is hampered by the low throughput and potential subjectivity of the visual evaluation of the parasite phenotypes, which affects the current drug assays. Here, an impedance-based platform, capable of assessing the viability of Schistosoma mansoni schistosomula exposed to drugs, is presented. This automated and parallelized platform enables unbiased and continuous measurements of dose-response relationships for more than 48 h. The platform performance is established by exposure of schistosomula to three test compounds, praziquantel, oxethazaine, and mefloquine, which are known to affect the larvae phenotypes. The system is thereafter used to investigate the response of schistosomula to methiothepine, an antipsychotic compound, which causes complex drug-induced effects. Continuous monitoring of the parasites reveals transient behavioral phenotypes and allows for extracting temporal characteristics of dose-response curves, which are essential for selecting drugs that feature high activity and fast kinetics of action. These measurements demonstrate that impedance-based detection provides a wealth of information for the in vitro characterization of candidate Antischistosomals and, represents a promising tool for the identification of new lead compounds.
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impedance based microfluidic assay for automated Antischistosomal drug screening
ACS Sensors, 2018Co-Authors: Ketki Chawla, Paolo S Ravaynia, Flavio C Lombardo, Mario M Modena, Gordana Panic, Martin Leonhardt, Sebastian C Burgel, Jennifer KeiserAbstract:Schistosomiasis is a neglected tropical disease, caused by parasitic worms, which affects almost 200 million people worldwide. For over 40 years, chemotherapeutic treatment has relied on the administration of praziquantel, an efficacious drug against schistosomiasis. However, concerns about developing drug resistance require the discovery of novel drug compounds. Currently, the drug-screening process is mostly based on the visual evaluation of drug effects on worm larvae in vitro by a trained operator. This manual process is extremely labor-intensive, has limited throughput, and may be affected by subjectivity of the operator evaluation. In this paper, we introduce a microfluidic platform with integrated electrodes for the automated detection of worm larvae viability using an impedance-based approach. The microfluidic analysis unit consists of two sets of electrodes and a channel of variable geometry to enable counting and size detection of single parasite larvae and the collective evaluation of the motility of the larvae as an unbiased estimator for their viability. The current platform also allows for multiplexing of the analysis units resulting in increased throughput. We used our platform to record size and motility variations of Schistosoma mansoni larvae exposed to different concentrations of mefloquine, a drug with established in vitro Antischistosomal properties. The developed platform demonstrates the potential of integrated microfluidic platforms for high-throughput Antischistosomal drug screening.
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assessment of tegumental damage to schistosoma mansoni and s haematobium after in vitro exposure to ferrocenyl ruthenocenyl and benzyl derivatives of oxamniquine using scanning electron microscopy
Parasites & Vectors, 2018Co-Authors: Jennifer Keiser, Valentin Buchter, Jeannine Hess, Gilles GasserAbstract:Schistosomiasis is one of the most harmful parasitic diseases worldwide, praziquantel being the only drug in widespread use to treat it. We recently demonstrated that ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine (Fc-OXA, Rc-OXA and Bn-OXA) are promising Antischistosomal drug candidates. In this study we assessed the tegumental damage of these three derivatives of oxamniquine using scanning electron microscopy. Adult Schistosoma mansoni and S. haematobium were exposed to a concentration of 100 μM of each drug and incubated for 4–120 h, according to their onset of action and activity. While on S. mansoni the fastest acting compound was Fc-OXA, which revealed high activity after 4 h of incubation, on S. haematobium, Rc-OXA revealed the quickest onset, being lethal on all males within 24 h. In both species studied, the three derivatives showed the same patterns of tegumental damage consisting of blebs, sloughing and tegument rupturing all over the body. Additionally, on S. mansoni distinct patterns of tegumental damage were observed for each of the compounds: tissue ruptures in the gynaecophoric canal for Fc-OXA, loss of spines for Rc-OXA and oral sucker rupture for Bn-OXA. Our study confirmed that Fc-OXA, Rc-OXA and Bn-OXA are promising broad spectrum Antischistosomal drug candidates. All derivatives show fast in vitro activity against S. mansoni and S. haematobium while validating the previous finding that the parent drug oxamniquine is less active in vitro under the conditions described. This work sets the base for further studies on the identification of a lead oxamniquine derivative, with the aim of identifying a molecule with the potential to become a new drug for human use.
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acting beyond 2020 better characterization of praziquantel and promising Antischistosomal leads
Current Opinion in Pharmacology, 2018Co-Authors: Jennifer Keiser, Gordana PanicAbstract:The commitment to eliminate schistosomiasis as a public health problem has mobilized the expansion of praziquantel treatment to meet the London Declaration targets. New research has thus sought to elucidate praziquantel's safety and efficacy in key demographics such as preschoolers and pregnant women, as well as novel elements of its pharmacokinetics and pharmacodynamics. At the same time, reliance on praziquantel ad infinitum would place schistosomiasis control at risk, should resistance occur. In response, the academic community has been filling the pre-clinical drug discovery pipeline with novel or resurrected drug candidates against schistosomiasis. In this review, we highlight the latest research on praziquantel treatment dynamics, which aims to improve the utility of this important drug. Moreover, we present the most promising preclinical Antischistosomal candidates, which should be studied further to achieve the ultimate goal- an alternative Antischistosomal drug in the near future.
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Synthesis, Characterization and Biological Activity of Organometallic Derivatives of the Antimalarial Drug Mefloquine as New Antischistosomal Drug Candidates
MedChemComm, 2018Co-Authors: Faustine D'orchymont, Jennifer Keiser, Jeannine Hess, Gordana Panic, Faustine D'orchymont, Marta Jakubaszek, Lea Gemperle, Gilles GasserAbstract:We present the design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the organic antimalarial mefloquine, a drug also known for its Antischistosomal activity. The two metallocenyl derivatives prepared (3 and 4) demonstrated comparable activity to mefloquine against adult-stage Schistosoma mansoni in vitro. Importantly, both compounds were found to have lower toxicity in all cell lines than mefloquine itself. Administration of a 200 mg/kg oral dose of 3 and 4 to S. mansoni-infected mice did not significantly reduce worm burden, contrary to mefloquine.
Mireille Vargas - One of the best experts on this subject based on the ideXlab platform.
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progress in Antischistosomal n n diaryl urea sar
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Chunkai Wang, Mireille Vargas, Karen L White, David M Shackleford, Gong Chen, Derek A Leas, Austin G Sanford, Ryan M Hemsley, Paul H DavisAbstract:Abstract N,N′-Diaryl ureas have recently emerged as a new Antischistosomal chemotype. We now describe physicochemical profiling, in vitro ADME, plasma exposure, and ex vivo and in vivo activities against Schistosoma mansoni for twenty new N,N′-diaryl ureas designed primarily to increase aqueous solubility, but also to maximize structural diversity. Replacement of one of the 4-fluoro-3-trifluoromethylphenyl substructures of lead N,N′-diaryl urea 1 with azaheterocycles and benzoic acids, benzamides, or benzonitriles decreased lipophilicity, and in most cases, increased aqueous solubility. There was no clear relationship between lipophilicity and metabolic stability, although all compounds with 3-trifluoromethyl-4-pyridyl substructures were metabolically stable. N,N′-diaryl ureas containing 4-fluoro-3-trifluoromethylphenyl, 3-trifluoromethyl-4-pyridyl, 2,2-difluorobenzodioxole, or 4-benzonitrile substructures had high activity against ex vivo S. mansoni and relatively low cytotoxicity. N,N-diaryl ureas with 3-trifluoromethyl-4-pyridyl and 2,2-difluorobenzodioxole substructures had the highest exposures whereas those with 4-fluoro-3-trifluoromethylphenyl substructures had the best in vivo Antischistosomal activities. There was no direct correlation between compound exposure and in vivo activity.
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Antischistosomal activity of pyrido 1 2 a benzimidazole derivatives and correlation with inhibition of β hematin formation
ACS Infectious Diseases, 2017Co-Authors: John Okombo, Kawaljit Singh, Godfrey Mayoka, Ferdinand Ndubi, Linley Barnard, Peter Njogu, Mathew Njoroge, Liezl Gibhard, Christel Brunschwig, Mireille VargasAbstract:The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro Antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit β-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent. At 10 μM, 48/57 compounds resulted in >70% mortality of newly transformed schistosomula, whereas 37 of these maintained >60% mortality of adult S. mansoni. No correlations were observed between β-hematin inhibitory and Antischistosomal activities against both larval and adult parasites, suggesting possible presence of other target(s) or a mode of inhibition of crystal formation that is not adequately modeled by the assay. The most ...
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revisiting the sar of the Antischistosomal aryl hydantoin ro 13 3978
Journal of Medicinal Chemistry, 2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K Chiu, Yuxiang DongAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising Antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high Antischistosomal activity. We identified several compounds with high Antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimizati...
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discovery of Antischistosomal drug leads based on tetraazamacrocyclic derivatives and their metal complexes
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: M Faruk O Khan, Mireille Vargas, Jennifer Keiser, Prince N A Amoyaw, Mohammad Faisal Hossain, Natalie C Simpson, Kimberly D Roewe, Tarynn Carder N FreemanAbstract:Praziquantel (PZQ) is the only drug available for the treatment of schistosomiasis, and since its large-scale use might be associated with the onset of resistance, new Antischistosomal drugs should be developed. A series of 26 synthetic tetraazamacrocyclic derivatives and their metal complexes were synthesized, characterized, and screened for Antischistosomal activity by application of a phased screening program. The compounds were first screened against newly transformed schistosomula (NTS) of harvested Schistosoma mansoni cercariae, then against adult worms, and finally, in vivo using the mouse model of S. mansoni infection. At a concentration of 33 μM, incubation with a total of 12 compounds resulted in the mortality of NTS at the 62% to 100% level. Five of these showing 100% inhibition of viability of NTS at 10 μM were selected for further screening for determination of the 50 inhibitory concentrations (IC50s) against both NTS and adult worms. Against NTS, all 5 compounds showed IC50s comparable to the IC50 of the standard drug, PZQ (0.87 to 9.65 μM for the 5 compounds versus 2.20 μM for PZQ). Three of these, which are the bisquinoline derivative of cyclen and its Fe(2+) and Mn(2+) complexes, showed micromolar IC50s (1.62 μM, 1.34 μM, and 4.12 μM, respectively, versus 0.10 μM for PZQ) against adult worms. In vivo, the worm burden reductions were 12.3%, 88.4%, and 74.5%, respectively, at a single oral dose of 400 mg/kg of body weight. The Fe(2+) complex exhibited activity in vivo comparable to that of PZQ, pointing to the discovery of a novel drug lead for schistosomiasis.
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activity profile of an fda approved compound library against schistosoma mansoni
PLOS Neglected Tropical Diseases, 2015Co-Authors: Gordana Panic, Mireille Vargas, Jennifer Keiser, Ivan ScandaleAbstract:As plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel Antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel Antischistosomal leads.; 1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies.; The in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively.; The work presented here expands the knowledge of Antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation.
Gilles Gasser - One of the best experts on this subject based on the ideXlab platform.
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assessment of tegumental damage to schistosoma mansoni and s haematobium after in vitro exposure to ferrocenyl ruthenocenyl and benzyl derivatives of oxamniquine using scanning electron microscopy
Parasites & Vectors, 2018Co-Authors: Jennifer Keiser, Valentin Buchter, Jeannine Hess, Gilles GasserAbstract:Schistosomiasis is one of the most harmful parasitic diseases worldwide, praziquantel being the only drug in widespread use to treat it. We recently demonstrated that ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine (Fc-OXA, Rc-OXA and Bn-OXA) are promising Antischistosomal drug candidates. In this study we assessed the tegumental damage of these three derivatives of oxamniquine using scanning electron microscopy. Adult Schistosoma mansoni and S. haematobium were exposed to a concentration of 100 μM of each drug and incubated for 4–120 h, according to their onset of action and activity. While on S. mansoni the fastest acting compound was Fc-OXA, which revealed high activity after 4 h of incubation, on S. haematobium, Rc-OXA revealed the quickest onset, being lethal on all males within 24 h. In both species studied, the three derivatives showed the same patterns of tegumental damage consisting of blebs, sloughing and tegument rupturing all over the body. Additionally, on S. mansoni distinct patterns of tegumental damage were observed for each of the compounds: tissue ruptures in the gynaecophoric canal for Fc-OXA, loss of spines for Rc-OXA and oral sucker rupture for Bn-OXA. Our study confirmed that Fc-OXA, Rc-OXA and Bn-OXA are promising broad spectrum Antischistosomal drug candidates. All derivatives show fast in vitro activity against S. mansoni and S. haematobium while validating the previous finding that the parent drug oxamniquine is less active in vitro under the conditions described. This work sets the base for further studies on the identification of a lead oxamniquine derivative, with the aim of identifying a molecule with the potential to become a new drug for human use.
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Synthesis, Characterization and Biological Activity of Organometallic Derivatives of the Antimalarial Drug Mefloquine as New Antischistosomal Drug Candidates
MedChemComm, 2018Co-Authors: Faustine D'orchymont, Jennifer Keiser, Jeannine Hess, Gordana Panic, Faustine D'orchymont, Marta Jakubaszek, Lea Gemperle, Gilles GasserAbstract:We present the design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the organic antimalarial mefloquine, a drug also known for its Antischistosomal activity. The two metallocenyl derivatives prepared (3 and 4) demonstrated comparable activity to mefloquine against adult-stage Schistosoma mansoni in vitro. Importantly, both compounds were found to have lower toxicity in all cell lines than mefloquine itself. Administration of a 200 mg/kg oral dose of 3 and 4 to S. mansoni-infected mice did not significantly reduce worm burden, contrary to mefloquine.
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toward organometallic Antischistosomal drug candidates
Future Medicinal Chemistry, 2015Co-Authors: Jeannine Hess, Jennifer Keiser, Gilles GasserAbstract:In the recent years, there has been a growing interest in the use of novel approaches for the treatment of parasitic diseases such as schistosomiasis. Among the different approaches used, organometallic compounds were found to offer unique opportunities in the design of antiparasitic drug candidates. A ferrocenyl derivative, namely ferroquine, has even entered clinical trials as a novel antimalarial. In this short review, we report on the studies describing the use of organometallic compounds against schistosomiasis.
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in vitro and in vivo Antischistosomal activity of ferroquine derivatives
Parasites & Vectors, 2014Co-Authors: Mireille Vargas, Jennifer Keiser, Gilles Gasser, Riccardo Rubbiani, Christophe BiotAbstract:Schistosomiasis is a neglected tropical disease and drug-repurposing is a useful strategy to fill its exhausted drug development pipeline. The ferrocenyl analogue of chloroquine, ferroquine, is an antimalarial in late-stage drug development. The aim of the present work was to study the Antischistosomal activity of ferroquine against Schistosoma mansoni adult worms and newly transformed schistosomula (NTS) in vitro and in vivo. Hydroxyl-ferroquine and ruthenoquine were included to study the potential role of reactive oxygen species in the Antischistosomal activity. Chloroquine and mefloquine, the later described for its Antischistosomal properties, served as comparators. All metal complexes were shown to be moderately cytotoxic on human cervix HeLa cancer cells and human fetal lung fibroblasts MRC-5. 72 hours post-incubation NTS exposed to 33.3 µM ruthenoquine had died, while ferroquine and hydroxyl-ferroquine treated worms were strongly affected. No activity was observed treating NTS with chloroquine at 33.3 µM. Incubation of adult S. mansoni with 33.3 µM of the organometallic derivatives were highly affected in viability but were still alive 72 hours post-incubation. Mefloquine showed the highest activity against NTS and adult S. mansoni. Low total worm burden reductions of 0-36% were observed following oral administration of 200–800 mg/kg of the ferroquine derivatives to S. mansoni-infected mice. The organometallic compounds evaluated in this study revealed moderate in vitro activity against both larval and adult stages of S. mansoni but low in vivo activity. No correlation can be drawn between the antimalarial and Antischistosomal activity of chloroquine analogues and oxidative shock does not seem to play a role in the activity of these compounds against S. mansoni.
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in vitro metabolic profile and in vivo Antischistosomal activity studies of η 6 praziquantel cr co 3 derivatives
Journal of Medicinal Chemistry, 2013Co-Authors: Malay Patra, Jennifer Keiser, Katrin Ingram, Anna Leonidova, Vanessa Pierroz, Stefano Ferrari, Murray N Robertson, Matthew H Todd, Gilles GasserAbstract:In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the Antischistosomal drug praziquantel (PZQ) with the formula (η(6)-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η(6)-PZQ)Cr(CO)3 derivatives (S, Sp)-1, (R, Rp)-1, (S, Rp)-2, and (R, Sp)-2 were also prepared to assess the eudysmic ratios of 1 and 2 against Schistosoma mansoni in vitro. A strong enantioselective Antischistosomal activity was observed. The R-enantiomers are highly active against adult schistosomes in vitro (IC50 0.08-0.13 μM), whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic S. mansoni infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24% and 29% (p > 0.05).
Katrin Ingram - One of the best experts on this subject based on the ideXlab platform.
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in vitro metabolic profile and in vivo Antischistosomal activity studies of η 6 praziquantel cr co 3 derivatives
Journal of Medicinal Chemistry, 2013Co-Authors: Malay Patra, Jennifer Keiser, Katrin Ingram, Anna Leonidova, Vanessa Pierroz, Stefano Ferrari, Murray N Robertson, Matthew H Todd, Gilles GasserAbstract:In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the Antischistosomal drug praziquantel (PZQ) with the formula (η(6)-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η(6)-PZQ)Cr(CO)3 derivatives (S, Sp)-1, (R, Rp)-1, (S, Rp)-2, and (R, Sp)-2 were also prepared to assess the eudysmic ratios of 1 and 2 against Schistosoma mansoni in vitro. A strong enantioselective Antischistosomal activity was observed. The R-enantiomers are highly active against adult schistosomes in vitro (IC50 0.08-0.13 μM), whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic S. mansoni infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24% and 29% (p > 0.05).
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in vivo Antischistosomal activity studies and in vitro metabolic profile of η6 praziquantel cr co 3 derivatives
Journal of Medicinal Chemistry, 2013Co-Authors: Malay Patra, Jennifer Keiser, Katrin Ingram, Anna Leonidova, Vanessa Pierroz, Stefano Ferrari, Murray N Robertson, Matthew H Todd, Gilles GasserAbstract:In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the Antischistosomal drug praziquantel (PZQ) with the formula (η6-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η6-PZQ)Cr(CO)3 derivatives (S, Sp)-1, (R, Rp)-1, (S, Rp)-2, and (R, Sp)-2 were also prepared to assess the eudysmic ratios of 1 and 2 against Schistosoma mansoni in vitro. A strong enantioselective Antischistosomal activity was observed. The R-enantiomers are highly active against adult schistosomes in vitro (IC50 0.08–0.13 μM), whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic S. mansoni infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24% and 29% (p > 0.05).
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identification of Antischistosomal leads by evaluating bridged 1 2 4 5 tetraoxanes alphaperoxides and tricyclic monoperoxides
Journal of Medicinal Chemistry, 2012Co-Authors: Jennifer Keiser, Katrin Ingram, Ivan A Yaremenko, Igor B Krylov, Lorenz Hofer, Alexander O TerentevAbstract:Although Antischistosomal properties of peroxides were studied in recent years, systematic structure–activity relationships have not been conducted. We evaluated the Antischistosomal potential of 6...
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Antischistosomal activities of mefloquine related arylmethanols
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Katrin Ingram, Jennifer Keiser, William Y EllisAbstract:Interesting Antischistosomal properties have been documented for the antimalarial mefloquine, a 4-quinolinemethanol. We evaluated the Antischistosomal activities of nine mefloquine-related compounds belonging to the 4-pyridinemethanols, 9-phenanthrenmethanols, and 4-quinolinemethanols. Eight compounds revealed high activities against Schistosoma mansoni in vitro, with two drugs (the 4-quinolinemethanols WR7573 and WR7930) characterized by significantly lower half-maximal inhibitory concentrations (IC50s) (2.7 and 3.5 μM, respectively) compared to mefloquine (11.4 μM). Mefloquine and WR7930 showed significantly decreased IC50s when incubated in the presence of hemoglobin. High worm burden reductions (WBR) were obtained with enpiroline (WBR, 82.7%; dosage, 200 mg/kg of body weight) and its threo isomers (+)-threo (WBR, 100%) and (−)-threo (WBR, 89%) and with WR7930 (WBR, 87%; dosage, 100 mg/kg) against adult S. mansoni in mice. Furthermore, excellent in vitro and in vivo Antischistosomal activity was observed for two WR7930-related structures (WR29252 and WR7524). In addition, mefloquine (WBR, 81%), enpiroline (WBR, 77%), and WR7930 (WBR, 100%) showed high activities against S. haematobium harbored in mice following single oral doses of 200 mg/kg. These results provide a deeper insight into the structural features of the arylmethanols that rule Antischistosomal activity. Further studies should be launched with enpiroline and WR7930.
Yuxiang Dong - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship of Antischistosomal ozonide carboxylic acids
Journal of Medicinal Chemistry, 2020Co-Authors: Xiaofang Wang, David M Shackleford, Francis C K Chiu, Sriraghavan Kamaraj, Vivek J Bulbule, Cecile Haberli, Eileen Ryan, Alexander I Wallick, Yuxiang DongAbstract:Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of Antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high Antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high Antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the Antischistosomal activity.
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revisiting the sar of the Antischistosomal aryl hydantoin ro 13 3978
Journal of Medicinal Chemistry, 2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K Chiu, Yuxiang DongAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising Antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high Antischistosomal activity. We identified several compounds with high Antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimizati...
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Antischistosomal versus antiandrogenic properties of aryl hydantoin ro 13 3978
American Journal of Tropical Medicine and Hygiene, 2014Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:In the early 1980s, the Antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95% and 64% total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between Antischistosomal activity and androgen receptor interaction.