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Hequan Yao - One of the best experts on this subject based on the ideXlab platform.
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Oxidation of 4-carboxylate thiazolines to 4-carboxylate thiazoles by molecular oxygen
Tetrahedron Letters, 2010Co-Authors: Yue Huang, Haifeng Gan, Hequan YaoAbstract:Abstract A facile and environment-benign oxidation by molecular oxygen was applied for the conversion of 4-carboxylate thiazolines to 4-carboxylate thiazoles. The substituent effect on thiazoline ring was investigated. It was found that electron-poor group on the thiazoline ring could facilitate the oxidation.
Michael Orfanopoulos - One of the best experts on this subject based on the ideXlab platform.
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stereochemistry in the reaction of 4 methyl 1 2 4 Triazoline 3 5 dione mtad with β β dimethyl p methoxystyrene are open biradicals the reaction intermediates
Journal of Organic Chemistry, 2001Co-Authors: Manolis Stratakis, Maria Hatzimarinaki, George E Froudakis, Michael OrfanopoulosAbstract:The reaction of 4-methyl-1,2,4-Triazoline-3,5-dione (MTAD) with β,β-dimethyl-p-methoxystyrene (1) in chloroform affords four adducts: the ene, two stereoisomeric [4 + 2]/ene diadducts, and a minor...
Pankaja K. Kadaba - One of the best experts on this subject based on the ideXlab platform.
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Rational Drug Design and the Discovery of the Δ2-1,2,3-Triazolines, A Unique Class of Anticonvulsant and Antiischemic Agents
Current medicinal chemistry, 2003Co-Authors: Pankaja K. KadabaAbstract:The delta(2)- 1,2,3- Triazoline anticonvulsants (TRs) may be considered as representing a unique class of "built-in" heterocyclic prodrugs where the active "structure element" is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead Triazoline, ADD17014 suggest that the Triazolines function as "prodrugs" and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-Glutamate (L-Glu) neurotransmission via a unique "dual-action" mechanism. While an active primary beta-amino alcohol metabolite from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK -801 receptor antagonist, the parent Triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence have led to the clucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, and their metabolic pathways, biotransformation products of TRs were predicted to be the beta-amino alcohols V and VA, the alpha-amino acid VI, the triazole VII, the aziridine VIII and the ketimine IX. In vivo and in vitro pharmacological studies of the TR and potential metabolites, along with a full quantitative urinary metabolic profiling of TR indicated the primary beta-amino alcohol V as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 micro M drug concentration, but itself had no anticonvulsant activity, suggesting TR acted as a prodrug. Three metabolites were identified; V was the most predominant (45.7 +/- 7.6) % of administered drug, with lesser amounts of VA, (17.3 +/- 5.1) % and very minor amounts of aziridine VIII (4.0 +/- 0.02)%. Since only VIII can yield VA, its formation indicated that the biotransformation of TR occurred, at least in part, through aziridine. No amino acid metabolite was detected, which implied that no in vivo oxidation of V or oxidative biotransformation of TR or aziridine by hydroxylation at the methylene group occurred. While Triazoline significantly decreased Ca(2+) -dependent, k(+)-evoked L-Glu release (83% at 100 micro M drug concentration ), some Triazolines showed an augmentation of 50-63%, in the Cl(-) channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of TRs in a variety of seizure models including their effectiveness in the kindling model of complex partial seizures may be due to their unique dual-action mechanism whereby the TR and V together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission; thus the TRs have clinical potential in the treatment of complex partial epilepsy which is refractory to currently available drugs. Since there is strong evidence that L-Glu plays an important role in human epilepsy as well as in brain ischemia/stroke, and since the TRs act by inhibiting EAA neurotransmission, it was logical to expect that the anticonvulsant TRs may evince beneficial therapeutic potential in cerebral ischemia resulting from stroke as well. And indeed, several TRs, when tested in the standard gerbil model of global ischemia did evince remarkable ability to prevent neuronal death.
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Triazolines xxvii δ2 1 2 3 Triazoline anticonvulsants novel built in heterocyclic prodrugs with a unique dual action mechanism for impairing excitatory amino acid l glutamate neurotransmission
Bioorganic & Medicinal Chemistry, 1996Co-Authors: Pankaja K. Kadaba, Paul J. Stevenson, Ivo Pnnane, L.a. DamaniAbstract:The delta2-1,2,3-Triazoline anticonvulsants (1) may be considered as representing a unique class of 'built-in' heterocyclic prodrugs where the active 'structure element' is an integral part of the ring system and can be identified only by a knowledge of their chemical reactivity and metabolism. Investigations on the metabolism and pharmacology of a lead Triazoline, ADD17014 (1a), suggest that the Triazolines function as 'prodrugs' and exert their anticonvulsant activity by impairing excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission via a unique 'dual-action' mechanism. While an active beta-amino alcohol metabolite, 2a, from the parent prodrug acts as an N-methyl-D-aspartate (NMDA)/MK-801 receptor antagonist, the parent Triazoline impairs the presynaptic release of L-Glu. Various pieces of theoretical reasoning and experimental evidence led to the elucidation of the dual-action mechanism. Based on the unique chemistry of the Triazolines, the potential metabolic pathways and biotransformation products of 1a were predicted to be the beta-amino alcohols 2a and 2a', the alpha-amino acid 3a, the triazole 4a, the aziridine 5a, and the ketimine 6a. In vivo and in vitro pharmacological studies of 1a and potential metabolities, along with a full quantitative urinary metabolic profiling of 1a, indicated the beta-amino alcohol 2a as the active species. It was the only compound that inhibited the specific binding of [3H]MK-801 to the MK-801 site, 56% at 10 microM drug concentration, but itself had no anticonvulsant activity, suggesting 1a acted as a prodrug. Three metabolites were identified; 2a was the most predominant, with lesser amounts of 2a', and very minor amounts of aziridine 5a. Since only 5a can yield 2a', its formation indicated that the biotransformation of 1a occurred, at least in part, through 5a. No amino acid metabolite 3a was detected, which implied that no in vivo oxidation of 2a or oxidative biotransformation of 1a or 5a by hydroxylation at the methylene group occurred. While Triazoline 1a significantly decreased Ca2(+)-dependent, K(+)-evoked L-Glu release (83% at 100 microM drug concentration), Triazolines 1a-1c showed an augmentation of 50-63%, in the Cl- channel activity, a useful membrane action that reduces the excessive L-Glu release that occurs during epileptic seizures. The high anticonvulsant activity of 1a may be due to its unique dual-action mechanism whereby 1a and 2a together effectively impair both pre- and postsynaptic aspects of EAA neurotransmission, and has clinical potential in complex partial epilepsy which is refractory to currently available drugs.
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Triazolines xxix 1 5 diaryl δ2 1 2 3 Triazolines as aphicides mechanism of action via aziridine formation
Pesticide Science, 1994Co-Authors: Pankaja K. KadabaAbstract:The aphicidal activity of 21 different 1,5-diphenyl-Δ2-1,2,3-Triazolines, conveniently prepared utilizing the catalytic effect of water on the 1,3-cyclo-addition of diazomethane to Schiff bases in aqueous dioxane, was evaluated. Triazolines bearing an o-Cl substituent on the C-phenyl, either alone (4) or in combination with a m- and/or a p-substituent on the N-phenyl (14, 15, 17 and 18), showed significant activity, with a combined m-, p- substitution on the N-phenyl the most effective (17 and 18). While an o-Cl substituent led to greater activity than an o-NO2 group, the introduction of an additional p-Cl substituent on the C-phenyl eliminated activity (21). The aphicidal activity of Triazoline 18 was found to be dependent on the presence of UV light. Since fluorescent lighting used in the testing procedure contains UV light and since Triazolines undergo photolysis when exposed to UV light to yield aziridines, it was logical to conclude that the aphicidal activity of the Triazolines was, in fact, derived from the aziridines formed during the testing procedure. This mechanism of action was confirmed by preparing the aziridines 22, 23 and 24 corresponding to the active Triazolines 14, 15 and 18, and showing that they possessed aphicidal activity equal to or better than that of the Triazolines, and by the activity observed in several other structurally related aziridine analogues (25–28). Unlike aziridinyl phosphorous compounds, the aziridines described here are not mutagenic in the Ames assay and thus afford a safer class of pesticides.
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Triazolines. XXI: Preformulation Degradation Kinetics and Chemical Stability of a Novel Triazoline Anticonvulsant
Journal of Pharmaceutical Sciences, 1992Co-Authors: M.a. Freeke Hamelijnck, Paul J. Stevenson, Pankaja K. Kadaba, L.a. DamaniAbstract:Abstract The effect of pH, temperature, and two buffer species (citric acid‐phosphate and bicarbonate‐carbonate) on the stability of 1‐(4‐chlorophenyl)‐5‐(4‐pyridyl)‐Δ 2 ‐1,2,3‐Triazoline (ADD17014; 1), a novel Triazoline anticonvulsant, was determined by HPLC. One of the main degradation products of 1 at pH 7.0 was isolated by TLC and identified as the aziridine derivative by MS. Investigations were carried out over a range of pH (2.2–10.7) and buffer concentration [ionic strength ( μ ), 0.25–4.18] at 23°C. The degradation followed buffer‐catalyzed, pseudo‐first‐order kinetics and was accelerated by a decrease in pH and an increase in temperature. The activation energy for the degradation in citric acid‐phosphate buffer (pH 7.0 and constant ionic strength μ at 0.54) was 12.5 kcal/mol. General acid catalysis was observed at pH 7.0 in citric acid‐phosphate buffer. The salt effect on the degradation obeyed the modified Debye‐Huckel equation well; however, the observed charge product ( Z A Z B ) value (2.69) deviated highly from the theoretical value (1.0), perhaps because of the high μ values (0.25–4.18) of the solutions used. The stability data will be useful in preformulation studies in the development of a stable, oral dosage form of 1.
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Triazolines xxiii high performance liquid chromatographic assay in rat blood for a novel Triazoline anticonvulsant add17014
Journal of Chromatography B: Biomedical Sciences and Applications, 1991Co-Authors: Paul J. Stevenson, M.a. Freeke Hamelijnck, Pankaja K. Kadaba, L.a. DamaniAbstract:A sensitive and specific high-performance liquid chromatographic (HPLC) method for the analysis of 1-(4-chlorophenyl)-5-(4-pyridyl)-Δ2-1,2,3-Triazoline (ADD17014, I), a novel anticonvulsant agent, in rat blood is described. Compound I and the internal standard (dipyridamole) were extracted into diethyl ether (5 ml) from alkalinised blood (0.25 ml of blood plus 0.75 ml of pH 10.7 buffer), with extractability nearing 100% under these conditions. The assay is based on reversed-phase HPLC (25 cm × 0.46 cm I.D. Spherisorb 5-ODS) using a mobile phase of methanol—acetonitrile—McIlvaine's citric acid—phosphate buffer (pH 8.0, 0.005 M) (30:30:40, v/v) and ultraviolet detection at 290 nm. Calibration curves were linear and reproducible (correlation coefficient > 0.999). Measurement of I in rat blood (250 μl sample size) was linear in the range 0–40 μg/ml and the coefficient of variation was less than 5%. The minimum detectable level was about 0.1 μg/ml; however, a larger blood sample size (1–2 ml) allowed measurement of levels as low as 10 ng/ml, especially for estimation of drug levels in samples withdrawn at later time points (24 h).
Gary W Breton - One of the best experts on this subject based on the ideXlab platform.
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acid catalyzed reaction of 4 methyl 1 2 4 Triazoline 3 5 dione metad with substituted benzenes
Tetrahedron Letters, 2011Co-Authors: Gary W BretonAbstract:The reaction of 4-methyl-1,2,4-Triazoline-3,5-dione (MeTAD) with substituted benzenes under the influence of trifluoroacetic acid catalysis was investigated. Generally, good-to-high yields of 1-arylurazoles resulting from aromatic substitution were obtained. Successful reaction required moderately electron-rich aromatics with proper substitution patterns. The reaction was tolerant of functionality on the aromatic ring.
Suelein Wang - One of the best experts on this subject based on the ideXlab platform.
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regio and diastereoselective ene reaction of 4 phenyl 1 2 4 Triazoline 3 5 dione with chiral allylic alcohols and their derivatives
Journal of Organic Chemistry, 1999Co-Authors: Ayhua Gau, Gueyliang Lin, Biingjiun Uang, Fenling Liao, Suelein WangAbstract:Chiral allylic alcohols 1a−e reacted with 4-phenyl-1,2,4-Triazoline-3,5-dione (PTAD) in CH2Cl2 to produce 3-amino-1-alken-4-ols 2 and 3 in 78−89% yields, with 68−90% diastereomeric excess (de) in f...
