A QSAR Study of the Antimalarial Activity of Some Synthetic 1,2,4-Trioxanes

Grigorov, Martin; Weber, Jacques; Tronchet, J. M. J.; Jefford, Charles W.; Milhous, Wilbur K.; Maric, Dj. M.

doi:10.1021/ci9601168

Cited by 44 publications

(40 citation statements)

References 16 publications

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“…In contrast an inactive analogue of artemisinin, deoxyartemisinin, docks in a different manner (51,52). Similar studies with synthetic endoperoxides suggest that docking between an active trioxane and the receptor, heme, is the crucial step for the drug action (53,54). In these studies, peroxide bond of the trioxane is found to lie close to the central iron atom of heme, suggesting it to be an important criterion for parasiticidal action.…”

Section: Discussionmentioning

confidence: 76%

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Pandey

Tekwani

Singh

et al. 1999

Journal of Biological Chemistry

225

156

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Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains.

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Section: Discussionmentioning

confidence: 76%

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Pandey

Tekwani

Singh

et al. 1999

Journal of Biological Chemistry

225

156

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“…Caso a estrutura do complexo receptor-fármaco seja conhecida, as interações entre ambos podem ser investigadas com mais detalhes. Estudos computacionais e quantitativos que correlacionam a estrutura química e a atividade biológica de uma série de fármacos e análogos têm apontado para os mecanismos de ação e têm dado diretrizes para a síntese de novos derivados mais eficientes [11][12][13][14][15][16][17] . No caso específico do tratamento da malária com artemisinina, há evidências experimentais de que o mecanismo de ação do fármaco envolve a formação de um complexo de transição heme-artemisinina.…”

Section: Figura 1 Estrutura Do Hemeunclassified

Estudo teórico da interação existente entre a artemisinina e o heme

Costa¹,

Kiralj²,

Ferreira³

2007

Quím. Nova

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Recebido em 22/8/05; aceito em 25/4/06; publicado na web em 30/8/06 THEORETICAL STUDY OF THE INTERACTION BETWEEN ARTEMISININ AND HEME. The purpose of this work is to study theoretically stereoelectronic aspects of the interaction between heme and artemisinin in the transitional heme-artemisinin complex. Through semi-empirical calculations using the PM3 method, the potential energy barrier of artemisinin rotation relative to heme in the heme-artemisinin complex was studied in vacuum and in the partially solvated state. The minimum heat of formation obtained for the complex with and without water molecules is -702.39 and -100.86 kcal mol -1 , respectively, which corresponds to the dihedral angle CFe-O1-O2 of 43.93º and 51.90º around the iron-oxygen O1 bond, respectively. The water molecules bind to heme via 13 hydrogen . It is observed that the inclusion of water molecules does not affect significantly the stability of the heme-artemisinin complex.Keywords: artemisinin; heme; PM3. INTRODUÇÃODe acordo com a Organização Mundial de Saúde, hoje em dia, a malária é de longe a doença tropical e parasitária que mais causa problemas sociais e econômicos no mundo e só é superada em nú-mero de mortes pela AIDS. A malária ainda é uma das doenças que mais crescem no mundo. O Plasmodium falciparum, responsável pela malária mais grave, afeta severamente a população mundial, causando de 1-1,5 milhões de mortes a cada ano, sendo a maioria crianças de até 5 anos de idade 1 . A malária ocorre principalmente nos países da África, Ásia e América Latina, devido às inadequadas estruturas na área da saúde e baixas condições socioeconômicas.Na . Após a infecção do indiví-duo pela picada do mosquito, os parasitas Plasmodium primeiramente se acumulam nos hepatócitos (células do fígado) na forma de esporozoítos, onde se desenvolvem e tornam-se merozoítos. Em seguida, os merozoítos invadem os eritrócitos para o próximo estágio de sua maturação. Neste estágio os merozoítos desenvolvem-se, tornando-se trofozoítos maduros (forma anelar) e, em seguida, tornamse esquizontes. Após alguns dias, as células vermelhas infectadas arrebentam e os merozoítos são liberados, causando as febres perió-dicas da malária. Cada esquizonte libera de 8-24 merozoítos e estes infectam novos eritrócitos, dando seqüência a um ciclo 4 . Dentro dos eritrócitos o parasita degrada grande parte da hemoglobina, liberando uma porção protéica (globina) e o heme (complexo ferro-porfirina). Em humanos, os parasitas da malária digerem mais de 70% da hemoglobina dentro das células vermelhas infectadas do sangue 5 . Cerca de 30% ou mais desta globina é digerida pelo parasita e usada como fonte de aminoácidos para a síntese de suas próprias proteínas. O heme proveniente da hemoglobina é tóxico para o parasita, que o converte no pigmento malarial. Neste processo, o parasita é destoxificado ao polimerizar o heme, com o auxílio da enzima heme polimerase, produzindo o pigmento da malária (hemozoína) 6 . A Figura 1 mostra a estrutura do heme, onde o átomo de Fe se encontra no estado de ...

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“…Structures of the 4-quiniolinecarbinolamines were imported into CATALYST to create a training set, and energy was minimized to the closest local minimum with the generalized CHARMM-like force field as imple- considering each compound as an ensemble of conformers representing different accessible areas in 3D space. The "best searching procedure" was applied to select representative conformers within 10 kcal/mol of the global minimum (12). CATALYST allows the use of structure and activity data for a set of lead compounds to create a hypothesis characterizing the activity of the lead set.…”

Section: Mefloquine Analogsmentioning

confidence: 99%

The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-ResistantPlasmodium falciparumStrains

Dow¹,

Koenig

Wolf

et al. 2004

Antimicrob Agents Chemother

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The clinical potential of mefloquine has been compromised by reports of adverse neurological effects. A series of 4-quinolinecarbinolamines were compared in terms of neurotoxicity and antimalarial activity in an attempt to identify replacement drugs. Neurotoxicity (MTT [thiazolyl blue reduction] assay) was assessed by exposure of cultured embryonic rat neurons to graded concentrations of the drugs for 20 min. The 50% inhibitory concentration (IC 50 ) of mefloquine was 25 M, while those of the analogs were 19 to 200 M. The relative (to mefloquine) therapeutic indices of the analogs were determined after using the tritiated hypoxanthine assay for assessment of the antimalarial activity of the analogs against mefloquine-sensitive (W2) and -resistant (D6 and TM91C235) Plasmodium falciparum strains. Five analogs, WR157801, WR073892, WR007930, WR007333, and WR226253, were less neurotoxic than mefloquine and exhibited higher relative therapeutic indices (RTIs) against TM91C235 (2.9 to 12.2). Conventional quinoline antimalarials were generally less neurotoxic (IC 50 s of 400, 600, and 900 for amodiaquine, chloroquine, and quinine) or had higher RTIs (e.g., 30 for halofantrine against TM91C235). The neurotoxicity data for the 4-quinolinecarbinolamines were used to develop a three-dimensional (3D), function-based pharmacophore. The crucial molecular features correlated with neurotoxicity were a hydrogen bond acceptor (lipid) function, an aliphatic hydrophobic function, and a ring aromatic function specifically distributed in the 3D surface of the molecule. Mapping of the 3D structures of a series of structurally diverse quinolines to the pharmacophore allowed accurate qualitative predictions of neurotoxicity (or not) to be made. Extension of this in silico screening approach may aid in the identification of less-neurotoxic quinoline analogs.

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A QSAR Study of the Antimalarial Activity of Some Synthetic 1,2,4-Trioxanes

Cited by 44 publications

References 16 publications

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Estudo teórico da interação existente entre a artemisinina e o heme

The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-ResistantPlasmodium falciparumStrains

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