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117 results on '"Smilkstein, Martin J."'

2. 3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance

Author

Pou, Sovitj, primary, Winter, Rolf W., additional, Dodean, Rozalia A., additional, Liebman, Katherine, additional, Li, Yuexin, additional, Mather, Michael W., additional, Nepal, Binod, additional, Nilsen, Aaron, additional, Handford, Mason J., additional, Riscoe, Teresa M., additional, Laxson, Sydney, additional, Kirtley, Payton J., additional, Aleshnick, Maya, additional, Zakharov, Lev N., additional, Kelly, Jane X., additional, Smilkstein, Martin J., additional, Wilder, Brandon K., additional, Kortagere, Sandhya, additional, Vaidya, Akhil B., additional, Alday, P. Holland, additional, Doggett, J. Stone, additional, and Riscoe, Michael K., additional

Published
2024
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4. ELQ-331 as a prototype for extremely durable chemoprotection against malaria

Author

Smilkstein, Martin J., Pou, Sovitj, Krollenbrock, Alina, Bleyle, Lisa A., Dodean, Rozalia A., Frueh, Lisa, Hinrichs, David J., Li, Yuexin, Martinson, Thomas, Munar, Myrna Y., Winter, Rolf W., Bruzual, Igor, Whiteside, Samantha, Nilsen, Aaron, Koop, Dennis R., Kelly, Jane X., Kappe, Stefan H. I., Wilder, Brandon K., and Riscoe, Michael K.

Published
2019
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6. Discovery of dual function acridones as a new antimalarial chemotype

Author

Kelly, Jane X., Smilkstein, Martin J., Brun, Reto, Wittlin, Sergio, Cooper, Roland A., Lane, Kristin D., Janowsky, Aaron, Johnson, Robert A., Dodean, Rozalia A., Winter, Rolf, Hinrichs, David J., and Riscoe, Michael K.

Subjects
Antimalarials -- Dosage and administration -- Complications and side effects -- Research -- Usage, Drug resistance in microorganisms -- Risk factors -- Prevention -- Complications and side effects -- Drug therapy -- Research, Drug therapy, Combination -- Usage -- Research, Malaria -- Drug therapy -- Research -- Risk factors -- Complications and side effects -- Prevention, Environmental issues, Science and technology, Zoology and wildlife conservation, Drug therapy, Prevention, Usage, Complications and side effects, Research, Risk factors, Dosage and administration
Abstract

Preventing and delaying the emergence of drug resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug-resistant malaria. Haem remains an immutable and vulnerable target, because it is not parasite-encoded and its detoxification during haemoglobin degradation, critical to parasite survival, can be subverted by drug--haem interaction as in the case of quinolines and many other drugs (1-5). Here we describe a new antimalarial chemotype that combines the haem-targeting character of acridones, together with a chemosensitizing component that counteracts resistance to quinoline antimalarial drugs. Beyond the essential intrinsic characteristics common to deserving candidate antimalarials (high potency in vitro against pan-sensitive and multi-drug-resistant Plasmodium falciparum, efficacy and safety in vivo after oral administration, inexpensive synthesis and favourable physicochemical properties), our initial lead, T3.5 (3-chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)acridone), demonstrates unique synergistic properties. In addition to 'verapamil-like' chemosensitization to chloroquine and amodiaquine against quinoline-resistant parasites, T3.5 also results in an apparently mechanistically distinct synergism with quinine and with piperaquine. This synergy, evident in both quinoline-sensitive and quinoline-resistant parasites, has been demonstrated both in vitro and in vivo. In summary, this innovative acridone design merges intrinsic potency and resistance-counteracting functions in one molecule, and represents a new strategy to expand, enhance and sustain effective antimalarial drug combinations., While feeding in the host red blood cell, malaria parasites ingest and degrade vast amounts of haemoglobin as a source of amino acids, consequently releasing toxic free haem as a [...]

Published
2009

9. Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

Author

Kancharla, Papireddy, primary, Dodean, Rozalia A., additional, Li, Yuexin, additional, Pou, Sovitj, additional, Pybus, Brandon, additional, Melendez, Victor, additional, Read, Lisa, additional, Bane, Charles E., additional, Vesely, Brian, additional, Kreishman-Deitrick, Mara, additional, Black, Chad, additional, Li, Qigui, additional, Sciotti, Richard J., additional, Olmeda, Raul, additional, Luong, Thu-Lan, additional, Gaona, Heather, additional, Potter, Brittney, additional, Sousa, Jason, additional, Marcsisin, Sean, additional, Caridha, Diana, additional, Xie, Lisa, additional, Vuong, Chau, additional, Zeng, Qiang, additional, Zhang, Jing, additional, Zhang, Ping, additional, Lin, Hsiuling, additional, Butler, Kirk, additional, Roncal, Norma, additional, Gaynor-Ohnstad, Lacy, additional, Leed, Susan E., additional, Nolan, Christina, additional, Ceja, Frida G., additional, Rasmussen, Stephanie A., additional, Tumwebaze, Patrick K., additional, Rosenthal, Philip J., additional, Mu, Jianbing, additional, Bayles, Brett R., additional, Cooper, Roland A., additional, Reynolds, Kevin A., additional, Smilkstein, Martin J., additional, Riscoe, Michael K., additional, and Kelly, Jane X., additional

Published
2020
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10. Targeted Structure-Activity Analysis of Endochin-like Quinolones Reveals Potent Qi and Qo Site Inhibitors of Toxoplasma gondii and Plasmodium falciparum Cytochrome bc(1) and Identifies ELQ-400 as a Remarkably Effective Compound against Acute Experimental Toxoplasmosis

Author

McConnell, Erin V., Bruzual, Igor, Pou, Sovitj, Winter, Rolf, Dodean, Rozalia A., Smilkstein, Martin J., Krollenbrock, Alina, Nilsen, Aaron, Zakharov, Lev N., Riscoe, Michael K., and Doggett, J. Stone

Subjects
Molecular Structure, Phenyl Ethers, Plasmodium falciparum, Antiprotozoal Agents, Drug Resistance, Quinolones, Article, Electron Transport Complex III, Mice, Structure-Activity Relationship, parasitic diseases, Drug Discovery, Animals, Humans, Malaria, Falciparum, Toxoplasma, Cells, Cultured, Toxoplasmosis
Abstract

Cytochrome bc(1) inhibitors have been broadly studied as human and veterinary medicines, and agricultural fungicides. For the most part, cytochrome bc(1) inhibitors compete with ubiquinol at the ubiquinol oxidation (Qo) site or with ubiquinone at the quinone reduction (Qi) site. 4(1H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1H)-Quinolones that inhibit the Qi site are highly effective against toxoplasmosis, malaria and babesiosis and do not inhibit human cytochrome bc(1). We tested a series of 4(1H)-Quinolones against wild-type and drug resistant strains of Toxplasma gondii and Plasmodium falciparum. These experiments identified very potent compounds that inhibit T. gondii proliferation at picomolar concentrations. The most potent compounds target the Qo site, and for these compounds, an alkyl side chain confers potency against T. gondii greater than that of bulkier side chains. Our experiments also show that substituents on the quinolone ring influenced selectivity between T. gondii and P. falciparum and between Qo and Qi site-mediated activity. Comparison of the parasite cytochrome b sequences identified amino acids that are associated with drug resistance in P. falciparum that exist naturally in wild-type T. gondii. These underlying differences may influence drug susceptibility. Finally, a Qo site active 4(1H)-quinolone-3-diarylether tested in a murine model of toxoplasmosis was superior to atovaquone, resulting in survival from Type I strain T. gondii infection. These experiments identify highly effective compounds for toxoplasmosis and provide valuable insight into the structure-activity relationship of cytochrome bc(1) inhibitors.

Published
2018

11. ELQ-331 as a prototype for extremely durable chemoprotection against malaria

Author

Smilkstein, Martin J., primary, Pou, Sovitj, additional, Krollenbrock, Alina, additional, Bleyle, Lisa A., additional, Dodean, Rozalia A., additional, Frueh, Lisa, additional, Hinrichs, David J., additional, Li, Yuexin, additional, Martinson, Thomas, additional, Munar, Myrna Y., additional, Winter, Rolf W., additional, Bruzual, Igor, additional, Whiteside, Samantha, additional, Nilsen, Aaron, additional, Koop, Dennis R., additional, Kelly, Jane X., additional, Kappe, Stefan H. I., additional, Wilder, Brandon K., additional, and Riscoe, Michael K., additional

Published
2019
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12. Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Author

Dodean, Rozalia A., primary, Kancharla, Papireddy, additional, Li, Yuexin, additional, Melendez, Victor, additional, Read, Lisa, additional, Bane, Charles E., additional, Vesely, Brian, additional, Kreishman-Deitrick, Mara, additional, Black, Chad, additional, Li, Qigui, additional, Sciotti, Richard J., additional, Olmeda, Raul, additional, Luong, Thu-Lan, additional, Gaona, Heather, additional, Potter, Brittney, additional, Sousa, Jason, additional, Marcsisin, Sean, additional, Caridha, Diana, additional, Xie, Lisa, additional, Vuong, Chau, additional, Zeng, Qiang, additional, Zhang, Jing, additional, Zhang, Ping, additional, Lin, Hsiuling, additional, Butler, Kirk, additional, Roncal, Norma, additional, Gaynor-Ohnstad, Lacy, additional, Leed, Susan E., additional, Nolan, Christina, additional, Huezo, Stephanie J., additional, Rasmussen, Stephanie A., additional, Stephens, Melissa T., additional, Tan, John C., additional, Cooper, Roland A., additional, Smilkstein, Martin J., additional, Pou, Sovitj, additional, Winter, Rolf W., additional, Riscoe, Michael K., additional, and Kelly, Jane X., additional

Published
2019
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14. Osmol gaps revisited: normal values and limitations

Author

Hoffman, Robert S., Smilkstein, Martin J., Howland, Mary Ann, and Goldfrank, Lewis R.

Subjects
Osmotic pressure -- Measurement, Alcohol -- Health aspects, Environmental issues, Health, Pharmaceuticals and cosmetics industries
Abstract

A study was designed to define the osmol gap in patients whose serum ethanol concentrations are known, to reevaluate several accepted equations for calculating osmolarity, and to apply the results to the theoretical clinical scenario of a toxic alcohol ingestion. The design for the study used consecutive, prospective enrollment of all patients presenting to a large inner city hospital who clinically required determination of their serum ethanol and electrolytes. Three hundred and twenty one consecutive adult patients were enrolled in the study, sixteen were excluded from the final analysis. A stepwise multiple linear regression analysis was performed to determine the best coefficients for sodium, blood urea nitrogen, and ethanol from the data set. Osmolarity was then calculated using these coefficients and traditional models. The osmol gap (measured osmolality minus calculated osmolarity [2*Na + BUN/2.8 + Glu/18 + Etoh/4.6]) was -2 [+ or -] 6 mOsm. Although different equations produced different osmol gaps (ranging from -5 to +15 mOsm) the standard deviations and correlation coefficients were similar. Large variations exist in the range of osmol gaps. Absolute values are very dependent on the equations used to calculate osmolarity. Because of the larger range of values, small osmol gaps should not be used to eliminate the possibility of toxic alcohol ingestion., INTRODUCTION The osmol gap is defined as the difference between the measured osmolality and the calculated osmolarity [1]. A calculation of the osmol gap is frequently suggested as a rapid [...]

Published
1993

15. Targeted Structure–Activity Analysis of Endochin-like Quinolones Reveals Potent Qi and Qo Site Inhibitors of Toxoplasma gondii and Plasmodium falciparum Cytochrome bc1 and Identifies ELQ-400 as a Remarkably Effective Compound against Acute Experimental Toxoplasmosis

Author

McConnell, Erin V., primary, Bruzual, Igor, additional, Pou, Sovitj, additional, Winter, Rolf, additional, Dodean, Rozalia A., additional, Smilkstein, Martin J., additional, Krollenbrock, Alina, additional, Nilsen, Aaron, additional, Zakharov, Lev N., additional, Riscoe, Michael K., additional, and Doggett, J. Stone, additional

Published
2018
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16. Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria

Author

Frueh, Lisa, primary, Li, Yuexin, additional, Mather, Michael W., additional, Li, Qigui, additional, Pou, Sovitj, additional, Nilsen, Aaron, additional, Winter, Rolf W., additional, Forquer, Isaac P., additional, Pershing, April M., additional, Xie, Lisa H., additional, Smilkstein, Martin J., additional, Caridha, Diana, additional, Koop, Dennis R., additional, Campbell, Robert F., additional, Sciotti, Richard J., additional, Kreishman-Deitrick, Mara, additional, Kelly, Jane X., additional, Vesely, Brian, additional, Vaidya, Akhil B., additional, and Riscoe, Michael K., additional

Published
2017
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27. Evaluation and lead optimization of anti-malarial acridones

Author

Winter, Rolf W., primary, Kelly, Jane X., additional, Smilkstein, Martin J., additional, Dodean, Rozalia, additional, Bagby, Grover C., additional, Rathbun, R. Keaney, additional, Levin, Joshua I., additional, Hinrichs, David, additional, and Riscoe, Michael K., additional

Published
2006
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29. APAP-induced heart injury? Maybe yes, maybe no. Next question?

Author

Smilkstein, Martin J.

Subjects
Acetaminophen -- Adverse and side effects, Heart, Environmental issues, Health, Pharmaceuticals and cosmetics industries
Abstract

There are two kinds of questions that remain unanswered. There are those that are important but difficult to resolve, and then there are others, less important, that keep coming up [...]

Published
1996

30. Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1Inhibition Strategy for Malaria

Author

Stickles, Allison M., Smilkstein, Martin J., Morrisey, Joanne M., Li, Yuexin, Forquer, Isaac P., Kelly, Jane X., Pou, Sovitj, Winter, Rolf W., Nilsen, Aaron, Vaidya, Akhil B., and Riscoe, Michael K.

Abstract

ABSTRACTAntimalarial combination therapies play a crucial role in preventing the emergence of drug-resistant Plasmodiumparasites. Although artemisinin-based combination therapies (ACTs) comprise the majority of these formulations, inhibitors of the mitochondrial cytochrome bc1complex (cyt bc1) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistant Plasmodium falciparumstrains with Qosite mutations. Here, we provide the first in vivocomparison of ATV, ELQ-300, and combination therapy consisting of ATV plus ELQ-300 (ATV:ELQ-300), using P. yoeliimurine models of malaria. In our monotherapy assessments, we found that ATV functioned as a single-dose curative compound in suppressive tests whereas ELQ-300 demonstrated a unique cumulative dosing effect that successfully blocked recrudescence even in a high-parasitemia acute infection model. ATV:ELQ-300 therapy was highly synergistic, and the combination was curative with a single combined dose of 1 mg/kg of body weight. Compared to the ATV:proguanil (Malarone) formulation, ATV:ELQ-300 was more efficacious in multiday, acute infection models and was equally effective at blocking the emergence of ATV-resistant parasites. Ultimately, our data suggest that dual-site inhibition of cyt bc1is a valuable strategy for antimalarial combination therapy and that Qisite inhibitors such as ELQ-300 represent valuable partner drugs for the clinically successful Qosite inhibitor ATV.

Published
2016
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