The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
David Leitsch - One of the best experts on this subject based on the ideXlab platform.
-
nitroimidazole drugs vary in their mode of action in the human parasite giardia lamblia
International Journal for Parasitology-Drugs and Drug Resistance, 2012Co-Authors: David Leitsch, Sarah Schlosser, Anita Burgess, Michael DuchêneAbstract:Giardia lamblia (syn. duodenalis, intestinalis) is a globally occurring micro-aerophilic human parasite that causes gastrointestinal disease. Standard treatment of G. lamblia infections is based on the 5-Nitroimidazole drugs metronidazole and tinidazole. In two other micro-aerophilic parasites, Entamoeba histolytica and Trichomonas vaginalis, 5-Nitroimidazole drugs bind to proteins involved in the thioredoxin-mediated redox network and disrupt the redox equilibrium by inhibiting thioredoxin reductase and depleting intracellular thiol pools. The major aim of this study was to assess whether nitroimidazoles exert a similar toxic effect on G. lamblia physiology. The 5-Nitroimidazoles metronidazole and tinidazole were found to bind to the same subset of proteins including thioredoxin reductase. However, in contrast to E. histolytica and T. vaginalis, none of the other proteins bound are candidates for being involved in the thioredoxin-mediated redox network. Translation elongation factor EF-1γ, an essential factor in protein synthesis, was widely degraded upon treatment with 5-Nitroimidazoles. 2-Nitroimidazole (azomycin) and the 5-Nitroimidazole ronidazole did not bind to any G. lamblia proteins, which is in contrast to previous findings in E. histolytica and T. vaginalis. All nitroimidazoles tested reduced intracellular thiol pools in G. lamblia, but metronidazole, also in contrast to the situation in the other two parasites, had the slightest effect. Taken together, our results suggest that nitroimidazole drugs affect G. lamblia in a fundamentally different way than E. histolytica and T. vaginalis.
-
disrupted intracellular redox balance of the diplomonad fish parasite spironucleus vortens by 5 nitroimidazoles and garlic derived compounds
Veterinary Parasitology, 2012Co-Authors: Catrin Ffion Williams, Kathirvel Alagesan, Michael Duchêne, Daniel Kolarich, Joanne Cable, David R. Williams, David LeitschAbstract:The 5-Nitroimidazole, metronidazole, has traditionally been employed in veterinary medicine to treat a range of infections including the diplomonad fish parasite Spironucleus. This study aims to determine the mode of action of metronidazole on Spironucleus vortens, including the specific mechanism of activation of the pro-drug and subsequent cellular targets of the drug metabolites. Due to the ban on use of metronidazole in the treatment of production animals in Europe and USA, garlic-derived compounds were also investigated as natural alternatives to metronidazole chemotherapy. Scanning electron microscopy (SEM) provided an overview of gross cellular damage caused by metronidazole and garlic derivatives. Proteomic analyses by 2D gel electrophoresis identified the proteins involved in specific covalent adduct formation with nitroimidazoles. Furthermore, thioredoxin reductase (TrxR) activity and non-protein thiol concentration were assayed in extracts of S. vortens before and after treatment with nitroimidazoles and garlic-derivatives. Metronidazole and garlic-derived compounds caused severe damage of trophozoites indicated by membrane blebbing and lysed cell debris. Analysis of the S. vortens proteome identified several proteins capable of specific nitroimidazole binding, including; uridine phosphorylase, enolase, protein disulphide isomerase, aminoacyl-histidine dipeptidase and malic enzyme. Of the compounds tested, metronidazole and the garlic-derived compound ajoene were the most effective at inhibiting TrxR activity and depleting non-protein thiols. These data suggest TrxR-mediated activation of nitroimidazoles, leading to depletion of non-protein thiols. Redox imbalance due to antioxidant failure is implicated as the mode of action of nitroimidazoles and garlic-derived compounds, ultimately leading to cell death. Possible synergy between garlic derivatives and metronidazole should be further investigated in vitro in order to determine their theoretical implications.
-
trichomonas vaginalis metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system implications for nitroimidazole toxicity and resistance
Molecular Microbiology, 2009Co-Authors: David Leitsch, Johannes Stadlmann, Friedrich Altmann, Marina Binder, Daniel Kolarich, Michael DuchêneAbstract:Summary Infections with the microaerophilic parasite Trichomonas vaginalis are treated with the 5-Nitroimidazole drug metronidazole, which is also in use against Entamoeba histolytica, Giardia intestinalis and microaerophilic/anaerobic bacteria. Here we report that in T. vaginalis the flavin enzyme thioredoxin reductase displays nitroreductase activity with nitroimidazoles, including metronidazole, and with the nitrofuran drug furazolidone. Reactive metabolites of metronidazole and other nitroimidazoles form covalent adducts with several proteins that are known or assumed to be associated with thioredoxin-mediated redox regulation, including thioredoxin reductase itself, ribonucleotide reductase, thioredoxin peroxidase and cytosolic malate dehydrogenase. Disulphide reducing activity of thioredoxin reductase was greatly diminished in extracts of metronidazole-treated cells and intracellular non-protein thiol levels were sharply decreased. We generated a highly metronidazole-resistant cell line that displayed only minimal thioredoxin reductase activity, not due to diminished expression of the enzyme but due to the lack of its FAD cofactor. Reduction of free flavins, readily observed in metronidazole-susceptible cells, was also absent in the resistant cells. On the other hand, iron-depleted T. vaginalis cells, expressing only minimal amounts of PFOR and hydrogenosomal malate dehydrogenase, remained fully susceptible to metronidazole. Thus, taken together, our data suggest a flavin-based mechanism of metronidazole activation and thereby challenge the current model of hydrogenosomal activation of nitroimidazole drugs.
Lars Eckmann - One of the best experts on this subject based on the ideXlab platform.
-
click chemistry facilitated comprehensive identification of proteins adducted by antimicrobial 5 nitroimidazoles for discovery of alternative drug targets against giardiasis
PLOS Neglected Tropical Diseases, 2020Co-Authors: Tineke Lauwaet, Sozaburo Ihara, Jaroslaw Kalisiak, Barry K Sharpless, Keith A. Korthals, Yukiko Miyamoto, Majid Ghassemian, Diane K Smith, Valery V Fokin, Lars EckmannAbstract:Giardiasis and other protozoan infections are major worldwide causes of morbidity and mortality, yet development of new antimicrobial agents with improved efficacy and ability to override increasingly common drug resistance remains a major challenge. Antimicrobial drug development typically proceeds by broad functional screens of large chemical libraries or hypothesis-driven exploration of single microbial targets, but both strategies have challenges that have limited the introduction of new antimicrobials. Here, we describe an alternative drug development strategy that identifies a sufficient but manageable number of promising targets, while reducing the risk of pursuing targets of unproven value. The strategy is based on defining and exploiting the incompletely understood adduction targets of 5-Nitroimidazoles, which are proven antimicrobials against a wide range of anaerobic protozoan and bacterial pathogens. Comprehensive adductome analysis by modified click chemistry and multi-dimensional proteomics were applied to the model pathogen Giardia lamblia to identify dozens of adducted protein targets common to both 5'-nitroimidazole-sensitive and -resistant cells. The list was highly enriched for known targets in G. lamblia, including arginine deiminase, α-tubulin, carbamate kinase, and heat shock protein 90, demonstrating the utility of the approach. Importantly, over twenty potential novel drug targets were identified. Inhibitors of two representative new targets, NADP-specific glutamate dehydrogenase and peroxiredoxin, were found to have significant antigiardial activity. Furthermore, all the identified targets remained available in resistant cells, since giardicidal activity of the respective inhibitors was not impacted by resistance to 5'-nitroimidazoles. These results demonstrate that the combined use of click chemistry and proteomics has the potential to reveal alternative drug targets for overcoming antimicrobial drug resistance in protozoan parasites.
-
nitroimidazole carboxamides as antiparasitic agents targeting giardia lamblia entamoeba histolytica and trichomonas vaginalis
European Journal of Medicinal Chemistry, 2016Co-Authors: Angie M Jarrad, Trpta Bains, Tomislav Karoli, Yukiko Miyamoto, Ruby Pelingon, Anjan Debnath, Mark S Butler, Michelle A Blaskovich, Karl A Hansford, Lars EckmannAbstract:Diarrhoeal diseases caused by the intestinal parasites Giardia lamblia and Entamoeba histolytica constitute a major global health burden. Nitroimidazoles are first-line drugs for the treatment of giardiasis and amebiasis, with metronidazole 1 being the most commonly used drug worldwide. However, treatment failures in giardiasis occur in up to 20% of cases and development of resistance to metronidazole is of concern. We have re-examined ‘old’ nitroimidazoles as a foundation for the systematic development of next-generation derivatives. Using this approach, derivatisation of the nitroimidazole carboxamide scaffold provided improved antiparasitic agents. Thirty-three novel nitroimidazole carboxamides were synthesised and evaluated for activity against G. lamblia and E. histolytica. Several of the new compounds exhibited potent activity against G. lamblia strains, including metronidazole-resistant strains of G. lamblia (EC50 = 0.1–2.5 μM cf. metronidazole EC50 = 6.1–18 μM). Other compounds showed improved activity against E. histolytica (EC50 = 1.7–5.1 μM cf. metronidazole EC50 = 5.0 μM), potent activity against Trichomonas vaginalis (EC50 = 0.6–1.4 μM cf. metronidazole EC50 = 0.8 μM) and moderate activity against the intestinal bacterial pathogen Clostridium difficile (0.5–2 μg/mL, cf. metronidazole = 0.5 μg/mL). The new compounds had low toxicity against mammalian kidney and liver cells (CC50 > 100 μM), and selected antiparasitic hits were assessed for human plasma protein binding and metabolic stability in liver microsomes to demonstrate their therapeutic potential.
Michael Duchêne - One of the best experts on this subject based on the ideXlab platform.
-
nitroimidazole drugs vary in their mode of action in the human parasite giardia lamblia
International Journal for Parasitology-Drugs and Drug Resistance, 2012Co-Authors: David Leitsch, Sarah Schlosser, Anita Burgess, Michael DuchêneAbstract:Giardia lamblia (syn. duodenalis, intestinalis) is a globally occurring micro-aerophilic human parasite that causes gastrointestinal disease. Standard treatment of G. lamblia infections is based on the 5-Nitroimidazole drugs metronidazole and tinidazole. In two other micro-aerophilic parasites, Entamoeba histolytica and Trichomonas vaginalis, 5-Nitroimidazole drugs bind to proteins involved in the thioredoxin-mediated redox network and disrupt the redox equilibrium by inhibiting thioredoxin reductase and depleting intracellular thiol pools. The major aim of this study was to assess whether nitroimidazoles exert a similar toxic effect on G. lamblia physiology. The 5-Nitroimidazoles metronidazole and tinidazole were found to bind to the same subset of proteins including thioredoxin reductase. However, in contrast to E. histolytica and T. vaginalis, none of the other proteins bound are candidates for being involved in the thioredoxin-mediated redox network. Translation elongation factor EF-1γ, an essential factor in protein synthesis, was widely degraded upon treatment with 5-Nitroimidazoles. 2-Nitroimidazole (azomycin) and the 5-Nitroimidazole ronidazole did not bind to any G. lamblia proteins, which is in contrast to previous findings in E. histolytica and T. vaginalis. All nitroimidazoles tested reduced intracellular thiol pools in G. lamblia, but metronidazole, also in contrast to the situation in the other two parasites, had the slightest effect. Taken together, our results suggest that nitroimidazole drugs affect G. lamblia in a fundamentally different way than E. histolytica and T. vaginalis.
-
disrupted intracellular redox balance of the diplomonad fish parasite spironucleus vortens by 5 nitroimidazoles and garlic derived compounds
Veterinary Parasitology, 2012Co-Authors: Catrin Ffion Williams, Kathirvel Alagesan, Michael Duchêne, Daniel Kolarich, Joanne Cable, David R. Williams, David LeitschAbstract:The 5-Nitroimidazole, metronidazole, has traditionally been employed in veterinary medicine to treat a range of infections including the diplomonad fish parasite Spironucleus. This study aims to determine the mode of action of metronidazole on Spironucleus vortens, including the specific mechanism of activation of the pro-drug and subsequent cellular targets of the drug metabolites. Due to the ban on use of metronidazole in the treatment of production animals in Europe and USA, garlic-derived compounds were also investigated as natural alternatives to metronidazole chemotherapy. Scanning electron microscopy (SEM) provided an overview of gross cellular damage caused by metronidazole and garlic derivatives. Proteomic analyses by 2D gel electrophoresis identified the proteins involved in specific covalent adduct formation with nitroimidazoles. Furthermore, thioredoxin reductase (TrxR) activity and non-protein thiol concentration were assayed in extracts of S. vortens before and after treatment with nitroimidazoles and garlic-derivatives. Metronidazole and garlic-derived compounds caused severe damage of trophozoites indicated by membrane blebbing and lysed cell debris. Analysis of the S. vortens proteome identified several proteins capable of specific nitroimidazole binding, including; uridine phosphorylase, enolase, protein disulphide isomerase, aminoacyl-histidine dipeptidase and malic enzyme. Of the compounds tested, metronidazole and the garlic-derived compound ajoene were the most effective at inhibiting TrxR activity and depleting non-protein thiols. These data suggest TrxR-mediated activation of nitroimidazoles, leading to depletion of non-protein thiols. Redox imbalance due to antioxidant failure is implicated as the mode of action of nitroimidazoles and garlic-derived compounds, ultimately leading to cell death. Possible synergy between garlic derivatives and metronidazole should be further investigated in vitro in order to determine their theoretical implications.
-
trichomonas vaginalis metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system implications for nitroimidazole toxicity and resistance
Molecular Microbiology, 2009Co-Authors: David Leitsch, Johannes Stadlmann, Friedrich Altmann, Marina Binder, Daniel Kolarich, Michael DuchêneAbstract:Summary Infections with the microaerophilic parasite Trichomonas vaginalis are treated with the 5-Nitroimidazole drug metronidazole, which is also in use against Entamoeba histolytica, Giardia intestinalis and microaerophilic/anaerobic bacteria. Here we report that in T. vaginalis the flavin enzyme thioredoxin reductase displays nitroreductase activity with nitroimidazoles, including metronidazole, and with the nitrofuran drug furazolidone. Reactive metabolites of metronidazole and other nitroimidazoles form covalent adducts with several proteins that are known or assumed to be associated with thioredoxin-mediated redox regulation, including thioredoxin reductase itself, ribonucleotide reductase, thioredoxin peroxidase and cytosolic malate dehydrogenase. Disulphide reducing activity of thioredoxin reductase was greatly diminished in extracts of metronidazole-treated cells and intracellular non-protein thiol levels were sharply decreased. We generated a highly metronidazole-resistant cell line that displayed only minimal thioredoxin reductase activity, not due to diminished expression of the enzyme but due to the lack of its FAD cofactor. Reduction of free flavins, readily observed in metronidazole-susceptible cells, was also absent in the resistant cells. On the other hand, iron-depleted T. vaginalis cells, expressing only minimal amounts of PFOR and hydrogenosomal malate dehydrogenase, remained fully susceptible to metronidazole. Thus, taken together, our data suggest a flavin-based mechanism of metronidazole activation and thereby challenge the current model of hydrogenosomal activation of nitroimidazole drugs.
Yukiko Miyamoto - One of the best experts on this subject based on the ideXlab platform.
-
click chemistry facilitated comprehensive identification of proteins adducted by antimicrobial 5 nitroimidazoles for discovery of alternative drug targets against giardiasis
PLOS Neglected Tropical Diseases, 2020Co-Authors: Tineke Lauwaet, Sozaburo Ihara, Jaroslaw Kalisiak, Barry K Sharpless, Keith A. Korthals, Yukiko Miyamoto, Majid Ghassemian, Diane K Smith, Valery V Fokin, Lars EckmannAbstract:Giardiasis and other protozoan infections are major worldwide causes of morbidity and mortality, yet development of new antimicrobial agents with improved efficacy and ability to override increasingly common drug resistance remains a major challenge. Antimicrobial drug development typically proceeds by broad functional screens of large chemical libraries or hypothesis-driven exploration of single microbial targets, but both strategies have challenges that have limited the introduction of new antimicrobials. Here, we describe an alternative drug development strategy that identifies a sufficient but manageable number of promising targets, while reducing the risk of pursuing targets of unproven value. The strategy is based on defining and exploiting the incompletely understood adduction targets of 5-Nitroimidazoles, which are proven antimicrobials against a wide range of anaerobic protozoan and bacterial pathogens. Comprehensive adductome analysis by modified click chemistry and multi-dimensional proteomics were applied to the model pathogen Giardia lamblia to identify dozens of adducted protein targets common to both 5'-nitroimidazole-sensitive and -resistant cells. The list was highly enriched for known targets in G. lamblia, including arginine deiminase, α-tubulin, carbamate kinase, and heat shock protein 90, demonstrating the utility of the approach. Importantly, over twenty potential novel drug targets were identified. Inhibitors of two representative new targets, NADP-specific glutamate dehydrogenase and peroxiredoxin, were found to have significant antigiardial activity. Furthermore, all the identified targets remained available in resistant cells, since giardicidal activity of the respective inhibitors was not impacted by resistance to 5'-nitroimidazoles. These results demonstrate that the combined use of click chemistry and proteomics has the potential to reveal alternative drug targets for overcoming antimicrobial drug resistance in protozoan parasites.
-
click chemistry facilitated comprehensive identification of proteins adducted by antimicrobial 5 nitroimidazoles for discovery of alternative drug targets against giardiasis
PLOS Neglected Tropical Diseases, 2020Co-Authors: Tineke Lauwaet, Sozaburo Ihara, Christine Le, Jaroslaw Kalisiak, Barry K Sharpless, Keith A. Korthals, Yukiko Miyamoto, Majid Ghassemian, Diane K Smith, Valery V FokinAbstract:Giardiasis and other protozoan infections are major worldwide causes of morbidity and mortality, yet development of new antimicrobial agents with improved efficacy and ability to override increasingly common drug resistance remains a major challenge. Antimicrobial drug development typically proceeds by broad functional screens of large chemical libraries or hypothesis-driven exploration of single microbial targets, but both strategies have challenges that have limited the introduction of new antimicrobials. Here, we describe an alternative drug development strategy that identifies a sufficient but manageable number of promising targets, while reducing the risk of pursuing targets of unproven value. The strategy is based on defining and exploiting the incompletely understood adduction targets of 5-Nitroimidazoles, which are proven antimicrobials against a wide range of anaerobic protozoan and bacterial pathogens. Comprehensive adductome analysis by modified click chemistry and multi-dimensional proteomics were applied to the model pathogen Giardia lamblia to identify dozens of adducted protein targets common to both 5’-nitroimidazole-sensitive and -resistant cells. The target list was highly enriched for known targets in G. lamblia, including arginine deiminase, α-tubulin, carbamate kinase, and heat shock protein 90, demonstrating the utility of the approach. Importantly, over twenty potential novel drug targets were identified. Inhibitors of two representative new targets, NADP-specific glutamate dehydrogenase and peroxiredoxin, were found to have significant antigiardial activity in vitro and in vivo. Furthermore, all the identified targets remained available in resistant cells, since giardicidal activity of the respective inhibitors was not impacted by resistance to 5’-nitroimidazoles. These results demonstrate that the combined use of click chemistry and proteomics has the potential to reveal alternative drug targets for overcoming antimicrobial drug resistance in protozoan parasites.
-
nitroimidazole carboxamides as antiparasitic agents targeting giardia lamblia entamoeba histolytica and trichomonas vaginalis
European Journal of Medicinal Chemistry, 2016Co-Authors: Angie M Jarrad, Trpta Bains, Tomislav Karoli, Yukiko Miyamoto, Ruby Pelingon, Anjan Debnath, Mark S Butler, Michelle A Blaskovich, Karl A Hansford, Lars EckmannAbstract:Diarrhoeal diseases caused by the intestinal parasites Giardia lamblia and Entamoeba histolytica constitute a major global health burden. Nitroimidazoles are first-line drugs for the treatment of giardiasis and amebiasis, with metronidazole 1 being the most commonly used drug worldwide. However, treatment failures in giardiasis occur in up to 20% of cases and development of resistance to metronidazole is of concern. We have re-examined ‘old’ nitroimidazoles as a foundation for the systematic development of next-generation derivatives. Using this approach, derivatisation of the nitroimidazole carboxamide scaffold provided improved antiparasitic agents. Thirty-three novel nitroimidazole carboxamides were synthesised and evaluated for activity against G. lamblia and E. histolytica. Several of the new compounds exhibited potent activity against G. lamblia strains, including metronidazole-resistant strains of G. lamblia (EC50 = 0.1–2.5 μM cf. metronidazole EC50 = 6.1–18 μM). Other compounds showed improved activity against E. histolytica (EC50 = 1.7–5.1 μM cf. metronidazole EC50 = 5.0 μM), potent activity against Trichomonas vaginalis (EC50 = 0.6–1.4 μM cf. metronidazole EC50 = 0.8 μM) and moderate activity against the intestinal bacterial pathogen Clostridium difficile (0.5–2 μg/mL, cf. metronidazole = 0.5 μg/mL). The new compounds had low toxicity against mammalian kidney and liver cells (CC50 > 100 μM), and selected antiparasitic hits were assessed for human plasma protein binding and metabolic stability in liver microsomes to demonstrate their therapeutic potential.
Patrice Vanelle - One of the best experts on this subject based on the ideXlab platform.
-
2 4 disubstituted 5 nitroimidazoles potent against clostridium difficile
ChemMedChem, 2019Co-Authors: Cedric Spitz, Maxime D. Crozet, Fanny Mathias, Severine Pechine, Tri Hanh Dung Doan, Jean Innocent, Sylvain Pellissier, Carole Di Giorgio, Claire Janoir, Patrice VanelleAbstract:Metronidazole is one of the first-line treatments for non-severe Clostridium difficile infections (CDI). However, resistance limits its use in cases of severe and complicated CDI. Structure-activity relationships previously described for the 5-Nitroimidazole series have shown that functionalization at the 2- and 4-positions can impart better activity against parasites and anaerobic bacteria than metronidazole. Herein we report the synthesis of new 2,4-disubstituted 5-Nitroimidazole compounds that show potent antibacterial activity against C. difficile. We used a vicarious nucleophilic substitution of hydrogen (VNS) reaction to introduce a phenylmethylsulfone at the 4-position and a unimolecular radical nucleophilic substitution (SRN 1) reaction to introduce an ethylenic function at the 2-position of the 5-Nitroimidazole scaffold.
-
Designing New 5-Nitroimidazoles: Towards Safer Anti-infectious Agents
Letters in Drug Design & Discovery, 2014Co-Authors: Maxime Crozet, Thierry Terme, Patrice VanelleAbstract:5-Nitroimidazoles are drugs having both antiprotozoal and antibacterial activity, but show mutagenicity and development of resistance observed particularly with metronidazole. For the development of new potentially safer derivatives, we investigated new strategies of synthesis: such as Vicarious Nucleophilic Substitution of hydrogen (VNS), palladium-catalyzed cross-coupling reactions (Suzuki-Miyaura, Sonogashira…) and electron transfer reactions (Unimolecular Radical Nucleophilic Substitution (SRN1), TDAE methodology) applied in 5-Nitroimidazole series.
-
Rapid Synthesis of New 5‐Nitroimidazoles as Potential Antibacterial Drugs via VNS Procedure
Synthetic Communications, 2006Co-Authors: Maxime D. Crozet, Vincent Remusat, Christophe Curti, Patrice VanelleAbstract:Abstract Original 4‐arylsulfonylmethyl‐5‐nitroimidazoles were prepared by reacting four chloromethylaryl sulfones with 5‐nitroimidazole derivatives via a vicarious nucleophilic substitution (VNS) of hydrogen reaction.
-
5 nitroimidazole drugs effective against metronidazole resistant trichomonas vaginalis and giardia duodenalis
Antimicrobial Agents and Chemotherapy, 2006Co-Authors: Jacqueline Upcroft, Linda A Dunn, Janelle M Wright, Kamel Benakli, Peter Upcroft, Patrice VanelleAbstract:Metronidazole (Mz)-resistant Giardia and Trichomonas were inhibited by 1 of 30 new 5-Nitroimidazole drugs. Another five drugs were effective against some but not all of the Mz-resistant parasites. This study provides the incentive for the continued design of 5-Nitroimidazole drugs to bypass cross-resistance among established 5-nitromidazole antiparasitic drugs.
-
synthese par reactions srn1 de nouveaux 5 nitroimidazoles antiparasitaires et antibacteriens
European Journal of Medicinal Chemistry, 1991Co-Authors: Patrice Vanelle, M P Crozet, J Maldonado, Michel BarreauAbstract:Resume Le 1-methyl 2-chloromethyl 5-Nitroimidazole reagit par un mecanisme S RN 1 avec divers anions nitronate aliphatiques, cycliques ou heterocycliques pour conduire avec d'excellents rendement a une nouvelle classe de 5-Nitroimidazoles portant en position 2 une double liaison ethylenique trisubstituee. Les molecules synthetisees presentent une activite antiprotozoaire et antianaerobie in vitro et in vivo comparable a celle du metronidazole, ce qui a permis d'etablir certaines relations structure-activite.