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Gary H. Posner - One of the best experts on this subject based on the ideXlab platform.
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the survival times of malaria infected mice are prolonged more by several new two carbon linked artemisinin derived dimer carbamates than by the Trioxane antimalarial drug artemether
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Ryan C Conyers, Bryan T Mott, Abhai K Tripathi, David J Sullivan, Maxime A Siegler, Jennifer R Mazzone, Gary H. PosnerAbstract:Sixteen new artemisinin-derived 2-carbon-linked Trioxane dimers were prepared to study chemical structure/antimalarial activity relationships (SAR). Administering a very low single oral dose of only 5 mg/kg of dimer secondary alcohol 6a or 6b plus 15 mg/kg of mefloquine hydrochloride prolonged the lives of Plasmodium berghei-infected mice to an average of 25 days after infection. This ACT chemotherapy result is of high medicinal significance because the antimalarial efficacy of the popular Trioxane drug artemether (2) plus mefloquine under the same conditions was significantly lower (only 20 day average survival). NH-aryl carbamate derivatives 7e, 7i, and 7j of 2-carbon-linked dimer alcohol 6b also significantly outperformed artemether (2) in prolonging the survival times (25–27 days) of malaria-infected mice.
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a single low oral dose of a 5 carbon linked Trioxane dimer orthoester plus mefloquine cures malaria infected mice
ChemInform, 2012Co-Authors: Deuk Kyu Moon, Abhai K Tripathi, David J Sullivan, Maxime A Siegler, Sean Parkin, Gary H. PosnerAbstract:Trioxane dimer orthoesters (VI) and (VIII) are obtained in moderate overall yields from the natural Trioxane artemisinin.
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a single low oral dose of a 5 carbon linked Trioxane dimer orthoester plus mefloquine cures malaria infected mice
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Deuk Kyu Moon, Abhai K Tripathi, David J Sullivan, Maxime A Siegler, Sean Parkin, Gary H. PosnerAbstract:Four 5-carbon-linked Trioxane dimer orthoesters (6a–6d) have been prepared in 4 or 5 chemical steps from the natural Trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, Trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally.
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malaria infected mice are cured by a single low dose of a new silylamide Trioxane plus mefloquine
Pharmaceuticals, 2009Co-Authors: Lauren E Woodard, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Bryan T Mott, Gary H. PosnerAbstract:Three thermally and hydrolytically stable silylamide Trioxanes have been prepared from the natural Trioxane artemisinin in only five simple chemical steps and in at least 56% overall yield. Two of these new chemical entities completely cured malariainfected mice at a single oral dose of only 8 mg/kg combined with 24 mg/kg of mefloquine hydrochloride. The high efficacy of this ACT chemotherapy is considerably better than the efficacy using the popular Trioxane drug artemether plus mefloquine hydrochloride.
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malaria infected mice live until at least day 30 after a new monomeric Trioxane combined with mefloquine are administered together in a single low oral dose
Journal of Medicinal Chemistry, 2009Co-Authors: Lauren E Woodard, Theresa A. Shapiro, Wonsuk Chang, Xiaochun Chen, Jun O Liu, Gary H. PosnerAbstract:In only five simple steps and 48% overall yield from the natural Trioxane artemisinin, the thermally and hydrolytically stable Trioxane fluoroanilide 4b has been prepared. Upon one oral dose of only 6.8 mg/kg of monomeric Trioxane 4b combined with 20 mg/kg of mefloquine hydrochloride, all of the malaria-infected mice lived until at least day 30 post infection. Of the five mice in this surviving group, four (80%) were completely cured (no parasites in their blood) and one mouse had 4% blood parasitemia. Importantly, the efficacy of this ACT chemotherapy using monomeric Trioxane 4b plus mefloquine hydrochloride is considerably better than the efficacy under the same conditions using the popular Trioxane drug artemether plus mefloquine hydrochloride.
Theresa A. Shapiro - One of the best experts on this subject based on the ideXlab platform.
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malaria infected mice are cured by a single low dose of a new silylamide Trioxane plus mefloquine
Pharmaceuticals, 2009Co-Authors: Lauren E Woodard, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Bryan T Mott, Gary H. PosnerAbstract:Three thermally and hydrolytically stable silylamide Trioxanes have been prepared from the natural Trioxane artemisinin in only five simple chemical steps and in at least 56% overall yield. Two of these new chemical entities completely cured malariainfected mice at a single oral dose of only 8 mg/kg combined with 24 mg/kg of mefloquine hydrochloride. The high efficacy of this ACT chemotherapy is considerably better than the efficacy using the popular Trioxane drug artemether plus mefloquine hydrochloride.
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malaria infected mice live until at least day 30 after a new monomeric Trioxane combined with mefloquine are administered together in a single low oral dose
Journal of Medicinal Chemistry, 2009Co-Authors: Lauren E Woodard, Theresa A. Shapiro, Wonsuk Chang, Xiaochun Chen, Jun O Liu, Gary H. PosnerAbstract:In only five simple steps and 48% overall yield from the natural Trioxane artemisinin, the thermally and hydrolytically stable Trioxane fluoroanilide 4b has been prepared. Upon one oral dose of only 6.8 mg/kg of monomeric Trioxane 4b combined with 20 mg/kg of mefloquine hydrochloride, all of the malaria-infected mice lived until at least day 30 post infection. Of the five mice in this surviving group, four (80%) were completely cured (no parasites in their blood) and one mouse had 4% blood parasitemia. Importantly, the efficacy of this ACT chemotherapy using monomeric Trioxane 4b plus mefloquine hydrochloride is considerably better than the efficacy under the same conditions using the popular Trioxane drug artemether plus mefloquine hydrochloride.
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malaria infected mice are cured by a single oral dose of new dimeric Trioxane sulfones which are also selectively and powerfully cytotoxic to cancer cells
Journal of Medicinal Chemistry, 2009Co-Authors: Andrew S Rosenthal, Theresa A. Shapiro, Xiaochun Chen, Jun O Liu, Diana C West, Paul J Hergenrother, Gary H. PosnerAbstract:A new series of 6 dimeric Trioxane sulfones has been prepared from the natural Trioxane artemisinin in five or six chemical steps. One of these thermally and hydrolytically stable new chemical entities (4c) completely cured malaria-infected mice via a single oral dose of 144 mg/kg. At a much lower single oral dose of only 54 mg/kg combined with 13 mg/kg of mefloquine hydrochloride, this Trioxane dimer 4c as well as its parent Trioxane dimer 4b also completely cured malaria-infected mice. Both dimers 4c and 4b were potently and selectively cytotoxic toward five cancer cell lines.
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Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice.
Drug development research, 2009Co-Authors: Deuk Kyu Moon, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Gary H. PosnerAbstract:Three new 5-carbon-linked Trioxane dimer carboxylate esters have been prepared from the natural Trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used Trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure.
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antimalarial preclinical drug development a single oral dose of a 5 carbon linked Trioxane dimer plus mefloquine cures malaria infected mice
Drug Development Research, 2009Co-Authors: Deuk Kyu Moon, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Gary H. PosnerAbstract:Three new 5-carbon-linked Trioxane dimer carboxylate esters have been prepared from the natural Trioxane, artemisinin, in only three steps and 40–50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used Trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure. Drug Dev Res 71: 76–81, 2010. © 2009 Wiley-Liss, Inc.
Deuk Kyu Moon - One of the best experts on this subject based on the ideXlab platform.
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a single low oral dose of a 5 carbon linked Trioxane dimer orthoester plus mefloquine cures malaria infected mice
ChemInform, 2012Co-Authors: Deuk Kyu Moon, Abhai K Tripathi, David J Sullivan, Maxime A Siegler, Sean Parkin, Gary H. PosnerAbstract:Trioxane dimer orthoesters (VI) and (VIII) are obtained in moderate overall yields from the natural Trioxane artemisinin.
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a single low oral dose of a 5 carbon linked Trioxane dimer orthoester plus mefloquine cures malaria infected mice
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Deuk Kyu Moon, Abhai K Tripathi, David J Sullivan, Maxime A Siegler, Sean Parkin, Gary H. PosnerAbstract:Four 5-carbon-linked Trioxane dimer orthoesters (6a–6d) have been prepared in 4 or 5 chemical steps from the natural Trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, Trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally.
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Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice.
Drug development research, 2009Co-Authors: Deuk Kyu Moon, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Gary H. PosnerAbstract:Three new 5-carbon-linked Trioxane dimer carboxylate esters have been prepared from the natural Trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used Trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure.
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antimalarial preclinical drug development a single oral dose of a 5 carbon linked Trioxane dimer plus mefloquine cures malaria infected mice
Drug Development Research, 2009Co-Authors: Deuk Kyu Moon, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Gary H. PosnerAbstract:Three new 5-carbon-linked Trioxane dimer carboxylate esters have been prepared from the natural Trioxane, artemisinin, in only three steps and 40–50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used Trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure. Drug Dev Res 71: 76–81, 2010. © 2009 Wiley-Liss, Inc.
Nirbhay Kumar - One of the best experts on this subject based on the ideXlab platform.
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malaria infected mice are cured by a single low dose of a new silylamide Trioxane plus mefloquine
Pharmaceuticals, 2009Co-Authors: Lauren E Woodard, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Bryan T Mott, Gary H. PosnerAbstract:Three thermally and hydrolytically stable silylamide Trioxanes have been prepared from the natural Trioxane artemisinin in only five simple chemical steps and in at least 56% overall yield. Two of these new chemical entities completely cured malariainfected mice at a single oral dose of only 8 mg/kg combined with 24 mg/kg of mefloquine hydrochloride. The high efficacy of this ACT chemotherapy is considerably better than the efficacy using the popular Trioxane drug artemether plus mefloquine hydrochloride.
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Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice.
Drug development research, 2009Co-Authors: Deuk Kyu Moon, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Gary H. PosnerAbstract:Three new 5-carbon-linked Trioxane dimer carboxylate esters have been prepared from the natural Trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used Trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure.
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antimalarial preclinical drug development a single oral dose of a 5 carbon linked Trioxane dimer plus mefloquine cures malaria infected mice
Drug Development Research, 2009Co-Authors: Deuk Kyu Moon, Vandana Singhal, Nirbhay Kumar, Theresa A. Shapiro, Gary H. PosnerAbstract:Three new 5-carbon-linked Trioxane dimer carboxylate esters have been prepared from the natural Trioxane, artemisinin, in only three steps and 40–50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used Trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure. Drug Dev Res 71: 76–81, 2010. © 2009 Wiley-Liss, Inc.
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structure activity relationships of lactone ring opened analogs of the antimalarial 1 2 4 Trioxane artemisinin
Journal of Medicinal Chemistry, 1995Co-Authors: Gary H. Posner, Nirbhay Kumar, David J Mcgarvey, Steven R Meshnick, Wanida AsawamahasadkaAbstract:1,2,4-Trioxane benzylic ethers 8a-e were prepared as simplified, tricyclic versions of the clinically used tetracyclic antimalarial drug artemisinin (1). Five additional artemisinin analogs (9-11) were prepared. Neither water solubility (analogs 8e and 11b) nor chelating ability (analogs 9 and 10), however, produced Trioxanes of especially high in vitro antimalarial activity. Trioxane fluorobenzyl ether 8b is the most active in this series (more active than artemisinin) against Plasmodium falciparum parasites in vitro, with substantial activity also in mice infected with Plasmodium berghei parasites and with 10 times higher activity than artemisinin (1) in killing immature P. falciparum gametocytes.
Paul M Oneill - One of the best experts on this subject based on the ideXlab platform.
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piperidine dispiro 1 2 4 Trioxane analogues
ChemInform, 2009Co-Authors: Sunil Sabbani, Paul A Stocks, Gemma L Ellis, Jill Davies, Erik Hedenstrom, Stephen A Ward, Paul M OneillAbstract:Dispiro N-Boc-protected 1,2,4-Trioxane 2 was synthesised via Mo(acac)(2) catalysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting beta-hydroperoxy alcohol 10 with 2-adamantanone. N-Boc 1,2,4-Trioxane 2 was converted to the amine 1,2,4-Trioxane hydrochloride salt 3 which was subsequently used to prepare derivatives (4-7). Several of these novel 1,2,4-Trioxanes had nanomolar antimalarial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile derivative for the preparation of achiral arrays of Trioxane analogues with antimalarial activity.
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application of thiol olefin co oxygenation methodology to a new synthesis of the 1 2 4 Trioxane pharmacophore
Organic Letters, 2004Co-Authors: Paul M Oneill, Jill Davies, Stephen A Ward, Amira Mukhtar, Jamie F Bickley, Mario D Bachi, Paul A StocksAbstract:[reaction: see text] Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates alpha-hydroxyperoxides that can be condensed in situ with various ketones to afford a series of functionalized 1,2,4-Trioxanes in good yields. Manipulation of the phenylsulfenyl group in 4a allows for convenient modification to the spiro-Trioxane substituents, and we describe, for the first time, the preparation of a new class of antimalarial prodrug.
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knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial Trioxanes like artemisinin allows rational design of new antimalarial peroxides
Accounts of Chemical Research, 2004Co-Authors: Gary H. Posner, Paul M OneillAbstract:Evidence is reviewed elucidating the mechanism of iron-induced triggering of antimalarial Trioxanes. As prodrugs, Trioxanes undergo homolytic, inner-sphere, reductive cleavage by ferrous iron to form sequentially oxy radicals, carbon radicals, high-valent iron-oxo species, epoxides, aldehydes, and dicarbonyl compounds. One or more of these reactive intermediates and neutral alkylating agents likely kill the malaria parasites. Several new, orally active antimalarial peroxides have been designed rationally based on this fundamental mechanistic paradigm. Incorporating metabolism-blocking substituents also provides some new, potent, semi-synthetic artemisinin derivatives.
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asymmetric syntheses of enantiomeric 3 p fluorophenyl 1 2 4 Trioxane analogues of the antimalarial artemisinin
Tetrahedron Letters, 1999Co-Authors: Paul M Oneill, Jamie F Bickley, Alison Miller, Feodor Scheinmann, Gary H. PosnerAbstract:Abstract We have devised an asymmetric synthesis of chiral artemisinin analogues (+)- 4a and (−)- 4a that retain the tricyclic ring system found in the natural product. The key step in the preparation of (+)- 4a involves an asymmetric MgCl 2 promoted Michael addition of the ( R )-(−)pyrrolidinemethanol-derived enamine 8 to acrylonitrile. This gives the corresponding ketone 9 in 50% yield (>95% ee). Subsequent elaboration of 9 provides the Trioxane target (+)- 4a in greater than 85% ee. Enantiomeric Trioxane (−)- 4a was prepared in a similar manner using ( S )-(+)-pyrrolidinemethanol in the first step of the sequence.
