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John F Hartwig - One of the best experts on this subject based on the ideXlab platform.
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regio and enantioselective n allylations of imidazole Benzimidazole and purine heterocycles catalyzed by single component metallacyclic iridium complexes
ChemInform, 2009Co-Authors: Levi M Stanley, John F HartwigAbstract:Highly regio- and enantioselective iridium-catalyzed N-allylations of Benzimidazoles, imidazoles, and purines have been developed. N-Allylated Benzimidazoles and imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of Benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were also obtained in high yields (up to 91%) with high N9/N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of Benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustrate the effect of nucleophile pK(a) on the rate of iridium-catalyzed N-allylation reactions. Kinetic studies on the allylation of Benzimidazole catalyzed by metallacyclic iridium-phosphoramidite complexes, in combination with studies on the deactivation of these catalysts in the presence of heterocyclic nucleophiles, provide insight into the effects of the structures of the phosphoramidite ligands on the stability of the metallacyclic catalysts. The data obtained from these studies have led to the development of N-allylations of Benzimidazoles and imidazoles in the absence of an exogenous base.
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regio and enantioselective n allylations of imidazole Benzimidazole and purine heterocycles catalyzed by single component metallacyclic iridium complexes
Journal of the American Chemical Society, 2009Co-Authors: Levi M Stanley, John F HartwigAbstract:Highly regio- and enantioselective iridium-catalyzed N-allylations of Benzimidazoles, imidazoles, and purines have been developed. N-Allylated Benzimidazoles and imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of Benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were also obtained in high yields (up to 91%) with high N9/N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of Benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustra...
Peter Kern - One of the best experts on this subject based on the ideXlab platform.
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structured treatment interruption in patients with alveolar echinococcosis
Hepatology, 2004Co-Authors: Stefan Reuter, Andreas Buck, Burkhard J Manfras, Wolfgang Kratzer, Hanns M Seitz, Kassa Darge, Sven N Reske, Peter KernAbstract:In human alveolar echinococcosis (AE), Benzimidazoles are given throughout life because they are only parasitostatic. It has been a longstanding goal to limit treatment, and recent reports suggest that, in selected cases, Benzimidazoles may be parasitocidal. Previously, we showed that positron –emission tomography (PET) using [18F]fluoro-deoxyglucose discriminates active from inactive lesions in AE. We have now performed a 3-year prospective study in 23 patients and conducted a structured treatment interruption in those without signs of PET activity. Disease progression was further assessed by ultrasound, computerized tomography, laboratory parameters, and clinical examination.We found PET-negative lesions in 15 of 23 patients and Benzimidazoles were discontinued in these patients. After 18 months, patients were reevaluated, and, of the 15 initially PET-negative patients, 8 showed either new activity on PET (n = 6) or signs of clinical progression (n = 2). Reinitiation of Benzimidazoles halted parasite growth again. No further progression was detected after 36 months. PET had a sensitivity of 91% for the detection of active lesions. In conclusion, despite successful suppression of metabolic activity, in most cases Benzimidazoles do not kill the parasite. PET is a reliable tool for assessing metabolic activity and for timely detection of relapses. Neither duration of treatment, kind of treatment, lesion size, calcifications, or regressive changes reliably indicate parasite death. We discourage the discontinuation of Benzimidazoles in inoperable AE even after many years of treatment. However, patients with a poor compliance of Benzimidazole intake or patients suffering from side effects to Benzimidazoles might be assessed for PET negativity. If permanent discontinuation of Benzimidazoles is attempted, the course of disease should be followed by PET. (HEPATOLOGY 2004;39:509–517.)
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structured treatment interruption in patients with alveolar echinococcosis
Hepatology, 2004Co-Authors: Stefan Reuter, Andreas Buck, Burkhard J Manfras, Wolfgang Kratzer, Hanns M Seitz, Kassa Darge, Sven N Reske, Peter KernAbstract:In human alveolar echinococcosis (AE), Benzimidazoles are given throughout life because they are only parasitostatic. It has been a longstanding goal to limit treatment, and recent reports suggest that, in selected cases, Benzimidazoles may be parasitocidal. Previously, we showed that positron -emission tomography (PET) using [(18)F]fluoro-deoxyglucose discriminates active from inactive lesions in AE. We have now performed a 3-year prospective study in 23 patients and conducted a structured treatment interruption in those without signs of PET activity. Disease progression was further assessed by ultrasound, computerized tomography, laboratory parameters, and clinical examination. We found PET-negative lesions in 15 of 23 patients and Benzimidazoles were discontinued in these patients. After 18 months, patients were reevaluated, and, of the 15 initially PET-negative patients, 8 showed either new activity on PET (n = 6) or signs of clinical progression (n = 2). Reinitiation of Benzimidazoles halted parasite growth again. No further progression was detected after 36 months. PET had a sensitivity of 91% for the detection of active lesions. In conclusion, despite successful suppression of metabolic activity, in most cases Benzimidazoles do not kill the parasite. PET is a reliable tool for assessing metabolic activity and for timely detection of relapses. Neither duration of treatment, kind of treatment, lesion size, calcifications, or regressive changes reliably indicate parasite death. We discourage the discontinuation of Benzimidazoles in inoperable AE even after many years of treatment. However, patients with a poor compliance of Benzimidazole intake or patients suffering from side effects to Benzimidazoles might be assessed for PET negativity. If permanent discontinuation of Benzimidazoles is attempted, the course of disease should be followed by PET.
Marilyn E Scott - One of the best experts on this subject based on the ideXlab platform.
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genetic variability of the beta tubulin genes in Benzimidazole susceptible and resistant strains of haemonchus contortus
Genetics, 1994Co-Authors: Robin N Beech, Marilyn E ScottAbstract:Benzimidazole anthelmintics are the most common chemotherapeutic agents used to remove intestinal helminths from farm animals. The development of drug resistance within helminth populations is wide-spread and can render these drugs essentially useless. The mechanism of Benzimidazole resistance appears to be common to many species ranging from fungi to nematodes and involves alterations in the genes encoding beta-tubulin. During the selection process resulting in resistance, there must be quantitative changes in the population gene pool. Knowledge of these changes would indicate the mechanisms underlying the spread of resistance in the population, which in turn could be used to design more effective drug administration strategies. To this end we have identified allelic variation at two beta-tubulin genes in Haemonchus contortus using restriction map analysis of individual adults. Extremely high levels of variation were identified at both loci within a susceptible strain. In two independently derived Benzimidazole resistant strains, allele frequencies at both loci were significantly different from the susceptible strain but not from each other. The same alleles at both loci, in both resistant strains, were favored by selection with Benzimidazoles, suggesting that both loci are involved in determining Benzimidazole resistance. These data confirm that changes in allele frequency, rather than novel genetic rearrangements induced by exposure to the drug, explain the changes associated with Benzimidazole resistance. These results also show that any DNA based test for the development of Benzimidazole resistance must take into account the frequency of alleles present in the population and not simply test for the presence or absence of specific allelic types.
Umer Chaudhry - One of the best experts on this subject based on the ideXlab platform.
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emergence and the spread of the f200y Benzimidazole resistance mutation in haemonchus contortus and haemonchus placei from buffalo and cattle
Veterinary Parasitology, 2019Co-Authors: Qasim Ali, Imran Rashid, Muhammad Zubair Shabbir, Kashif Shahzad, Kamran Ashraf, Neil Sargison, Umer ChaudhryAbstract:Abstract Benzimidazoles have been intensively (for over 40 years) used in the livestock sector, particularly in small ruminants. This has been led to the widespread emergence of resistance in a number of small ruminant parasite species, especially Haemonchus contortus. In many countries Benzimidazole resistance has severely compromised the control of H. contortus in small ruminants; but there is a little information on Benzimidazole resistance in H. contortus infecting buffalo and cattle. Resistance to Benzimidazoles have also been reported in the large ruminant parasite, Haemonchus placei, but again there is relatively little information on its prevalence. Hence it is very important to understand how resistance-conferring mutations emerge and spread in both parasites in buffalo and cattle hosts in order to develop approaches for the recognition of the problem at an early stage of its development. The present study suggests that the F200Y (TAC) mutation is common in H. contortus, being detected in 5/7 populations at frequencies between 7 and 57%. Furthermore, 6/10 H. placei populations contained the F200Y (TAC) mutation, albeit at low frequencies of between 0.4 and 5%. The phylogenetic analysis suggests that the F200Y (TAC) mutation in H. contortus has emerged on multiple occasions in the region, with at least three independent emergences across the populations. In contrast, the F200Y (TAC) resistance-conferring mutation in H. placei is only seen on a single haplotype. A high level frequency of the resistance haplotypes in the region, suggests that the unique resistance conferring-mutation has spread from a single emergence; likely by anthropogenic animal movement. Overall, these results provide the first clear genetic evidence for the spread of Benzimidazole resistance-conferring mutations to multiple different locations from a single emergence in H. placei; while being consistent with previous small ruminant-based observations of multiple emergence of resistance mutations in H. contortus.
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emergence and the spread of the f200y Benzimidazole resistance mutation in haemonchus contortus and haemonchus placei from buffalo and cattle
bioRxiv, 2018Co-Authors: Qasim Ali, Imran Rashid, Muhammad Zubair Shabbir, Kashif Shahzad, Kamran Ashraf, Neil Sargison, Azizul Rahman, Umer ChaudhryAbstract:Benzimidazoles have been intensively used in the livestock sector, particularly in small ruminants for over 40 years. This has been led to the widespread emergence of resistance in a number of small ruminant parasite species, in particular Haemonchus contortus. In many counties Benzimidazole resistance in the small ruminants H. contortus has become severely compromising its control; but there is a little information on Benzimidazole resistance in H. contortus infecting buffalo and cattle. Resistance to Benzimidazoles have also been reported in the large ruminant parasite, Haemonchus placei, but again there is relatively little information on its prevalence. Hence it is extremely important to understand how resistance-conferring mutations emerge and spread in both parasites in the buffalo and cattle host in order to develop the approaches for the recognition of the problem at an early stage of its development. The present study suggests that the F200Y (TAC) mutation is common in H. contortus, being detected in 5/7 populations at frequencies between 7 to 57%. Furthermore, 6/10 H. placei populations contained the F200Y (TAC) mutation, albeit at low frequencies of between 0.4 to 5%. The phylogenetic analysis suggests that the F200Y (TAC) mutation in H. contortus has emerged on multiple occasions in the region, with at least three independent emergence of resistance alleles across the populations. In contrast, the F200Y (TAC) resistance-conferring mutation in H. placei is only seen on a single haplotype. A high level of haplotype frequency of the susceptible alleles in the region, suggests that the unique resistance conferring-mutation has spread from a single emergence; likely by anthropogenic animal movement. Overall, these results provide the first clear genetic evidence for the spread of Benzimidazoles resistance-conferring mutations to multiple different locations from a single emergence in H. placei; while supporting previous small ruminant-based observations of multiple emergence of resistance mutations in H. contortus. Keywords: H. placei, H. contortus, anthelmintic drug classes, Benzimidazole resistance.
Levi M Stanley - One of the best experts on this subject based on the ideXlab platform.
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regio and enantioselective n allylations of imidazole Benzimidazole and purine heterocycles catalyzed by single component metallacyclic iridium complexes
ChemInform, 2009Co-Authors: Levi M Stanley, John F HartwigAbstract:Highly regio- and enantioselective iridium-catalyzed N-allylations of Benzimidazoles, imidazoles, and purines have been developed. N-Allylated Benzimidazoles and imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of Benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were also obtained in high yields (up to 91%) with high N9/N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of Benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustrate the effect of nucleophile pK(a) on the rate of iridium-catalyzed N-allylation reactions. Kinetic studies on the allylation of Benzimidazole catalyzed by metallacyclic iridium-phosphoramidite complexes, in combination with studies on the deactivation of these catalysts in the presence of heterocyclic nucleophiles, provide insight into the effects of the structures of the phosphoramidite ligands on the stability of the metallacyclic catalysts. The data obtained from these studies have led to the development of N-allylations of Benzimidazoles and imidazoles in the absence of an exogenous base.
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regio and enantioselective n allylations of imidazole Benzimidazole and purine heterocycles catalyzed by single component metallacyclic iridium complexes
Journal of the American Chemical Society, 2009Co-Authors: Levi M Stanley, John F HartwigAbstract:Highly regio- and enantioselective iridium-catalyzed N-allylations of Benzimidazoles, imidazoles, and purines have been developed. N-Allylated Benzimidazoles and imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of Benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. N-Allylated purines were also obtained in high yields (up to 91%) with high N9/N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of Benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustra...