Latosińska, J. N.; Latosińska, M.; Utrecht, R.; Mielcarek, S.; Pietrzak, J.
The 1H solid state NMR spectra of four sulphonamide derivatives of 1,2,4-benzothiadiazine-1,1-dioxides (thiazides) were recorded at different temperatures in the range 100-400 K and the temperature dependencies of the second moment ( M2) of the resonant line and spin-lattice relaxation time ( T1) were measured. The minimum in the temperature dependence of the T1 revealed an activation process related to the hindered rotation (jumps) of the -NH 2 group. The activation energy of this motion estimated on the basis of the fit of the theoretical model to the experimental points was 36.5 kJ/mol for HCTZ, 31.8 kJ/mol for ATZ, 35.2 kJ/mol for TCTZ and 40.6 kJ/mol for CTZ, and was close to that calculated by the DFT (B3LYP/6-311+G(2d,p)) method for the model assuming the -NH 2 jumps between two equilibrium positions. This type motion is responsible for the reduction in the NMR line second moment by approximately 1Gs 2 observed for all the thiazides studied. Thiazides also perform a quasi-isotropic motion tumbling whose activation energy is higher than that of the hindered jumps of the NH 2 group. This motion is characterized only by M2 reduction. According to the increasing strength of the NH 2 group bonding in the crystalline lattice, the thiazides studied can be ordered as: ATZ
ZHONG, Wei-Hui; CHEN, Xiao-Yuan; ZHANG, Yong-Min
The intermolecular reductivc cyclization of o-nitrobenzene sulfonamides with aliphafic ketones induced by TiCl4/Sm sys tem was studied and a series of 3,3-disubstituted-3,4-dihydro (2H)-1, 2, 4-benzothiadiazine-1, 1-dioxides were synthesized in moderate to high yields under mild and neutral conditions.
Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides
Francotte, Pierre; Nørholm, Ann-Beth; Deva, Taru;
Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom...... on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological...
ATP-sensitive potassium channels (KATP) play an important role in many cellular processes. The modulation of these channels by activating molecules may constitute very interesting pharmacological and medicinal applications. For this purpose, we have designed and synthesized new hybrid molecules cromakalim-diazoxide and diazoxide-amine/aminoacid. We also evaluated the relaxant activity of these compounds on aorta of rats. The obtained results do not show a significant relaxant effect. Studies ...
Nørholm, Ann-Beth; Francotte, Pierre; Olsen, Lars
Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing...
Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure-Activity Relationship at AMPA Receptors
Larsen, Anja Probst; Francotte, Pierre; Frydenvang, Karla;
Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer's disease. Here, we report synthesis and pharmacological evaluation...
Schneider-Affeld, F; Rüttgers, H; Hter, J; Kubli, F
The tocolytic efficiency of Diazoxide, a benzothiadiazine derivative with pronounced musculotropic action, was tested on the isolated uteri of non-gravid and gravid rats. Regular uterine contractions were induced by the prostaglandines E2 and F2 alpha. Their amplitude and frequency could be suppressed totally or subtotally. Contraction intervals lasted 4--22 min. The basal tone was reduced in most cases.
Krintel, Christian; Francotte, Pierre; Pickering, Darryl S;
The 1,2,4-benzothiadiazine 1,1-dioxide type of positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) are promising lead compounds for the treatment of cognitive disorders, e.g., Alzheimer’s disease. The modulators bind in a cleft formed by the interface of two neighboring...
Jensen, J B; Pickering, D S; Schousboe, A;
was blocked by 6-chloro-3,4-dihydro-3-(2-norbornen-5-yl)-2H-1,2, 4-benzothiadiazine-7-sulphonamide-1,1-dioxide (cyclothiazide). Under the non-desensitizing conditions, the AMPA-induced release of [(3)H]D-aspartate was highly enhanced showing about a 10-fold increase over basal release. Addition of cobalt...
To elucidate the binding mechanism of the herbicide bentazon (3-isopropyl-1H-2,1,3-benzothiadiazine-4(3H)-one 2,2-dioxide) with humic monomers in the presence of an oxidative enzyme, the reaction of bentazon with catechol, caffeic acid, protocatechuic...
Chona, S; Triggle, D J
Diazoxide and four related 1,2,4-benzothiadiazines reduced the maximum responses to noradrenaline (NA) and KCl in aortic rings from normotensive and spontaneously hypertensive rats (SHR). These agents were more active against NA than against KCl responses, and more effective against either NA or KCl responses in aortae from hypertensive animals. Further studies with V (3-cyclopentenyl-6,7-dichloro-1,2,4-benzothiadiazine-1,1-dioxide), the most active member of the series, showed it to be significantly more effective against NA responses; when calcium was added to calcium-free solutions containing eith NA or KCl, V was more effective in inhibiting either response in SHR aortae and was about 100 times more effective in inhibiting the calcium-NA responses. These data are consistent with previous findings that vascular smooth muscle from normotensive and SHR differs in sensitivity to diazoxide. However, the site(s) at which this difference is exhibited remains to be elucidated.
Clausen, Liselotte; Fabricius, Ida Lykke; Madsen, L.
The fate of pesticides in aquifers is influenced by the small but not insignificant adsorption of pesticides to mineral surfaces. Batch experiments with five pesticides and four minerals were conducted to quantify the contributions to adsorption from different mineral surfaces and compare...... adsorption characteristics of selected pesticides. Investigated mineral phases included quartz, calcite, kaolinite, and alpha -alumina. Selected pesticides comprised atrazine (6-chloro-N-2-ethyl-N-4-isopropyl-1,3,5-triazine-2,4-diamine isoproturon [3-(4-isopropyl-phenyl)-1,1-dimethylurea)], mecoprop [(RS)-2......-(4-chloro-2-methyl phenoxy)propionic acid], 2,4-D (2,4-dichlorophenoxyacetic acid), and bentazone [3-isopropyl-1H-2,1,3-benzothiadiazin-4-(3H)-one 2,2-dioxide]. Specific surface area and mineral surface charge proved to be important for the adsorption of these pesticides. Detectable adsorption...
Huali Wang; Qiang Wang
Bentazon, with chemical name 3-isopropyl-lH-2,1,3-benzothiadiazin-4(3H)-one 2,2-dioxide,is a colorless to slightly brown,odorless crystalline solid.Bentazon is one of the synthetic,contact,and post-emergence herbicide used for selective control of broadleaf weeds and sedges in numerous crop fields.%Terahertz (THz) spectra of bentazon are determined within the range of 0.3-2.4 THz at room temperar ture. Density functional methods are used to compute the THz spectra using three different programs: GaussianO3 for isolated-molecule form, DMol3 and CRYSTAL09 for solid-state forms. Among the three, the computed THz spectrum of CRYSTAL09 shows better bond length and angle agreements with X-ray experimental results, and corresponds with observed THz experiment spectral characteristics. The isolated-molecule vibrational mode values are less by half than those derived from solid-state calculations. The last five peak positions of the two solid-state computations coincide with each other. Moreover, all the experimental THz absorption peaks are assigned by utilizing CRYSTAL09.
Latosińska, J. N.
The 13C MAS solid state NMR spectra of four sulphonamide derivatives of 1,2,4-benzothiadiazine-1,1-dioxides, commonly known as thiazides, were recorded and the chemical shifts and chemical shift anisotropy (CSA) were measured. Analysis of the experimental 13C shielding parameters was supported by DFT theoretical calculations carried out within the gauge-including atomic orbital (GIAO), semiempirical Typed Neglect of Differential Overlap (TNDO/2) approach and by the spectra estimations performed by ChemNMR Pro 6.0, ACD-I/LAB, SpecInfo and gNMR. It was found that the chemical shifts obtained with ChemNMR Pro 6.0, ACD-I/LAB, SpecInfo and gNMR were insensitive to the substitution effects, whereas the semiempirical TNDO/2 and density functional theory (DFT) B3LYP/6-311+G(2d,p) methods allowed estimation of the influence of substituents on the chemical shielding and consequently, the chemical shift. The influence of the substituents at C3 position of the ring on the chemical shifts was analysed on the basis of the experimental data and results of the DFT calculations. The values of the chemical shifts and the low values of the anisotropy parameter for the C3 atom in HCTZ, TCTZ and ATZ, strongly indicated that three thiazides HCTZ, TCTZ and ATZ occurred in the form of HCTZ type with the C3 carbon atom participating in a single bond. The following ordering of the substituents according to the increasing electron accepting properties was found: -H<-CH 2SCH 2CHCH 2<-CHCl 2. A detailed analysis of the inductive and coupling effects was made on the basis of 13C chemical shifts and chemical shielding tensor asymmetry parameters on the C3 and C6 carbon atoms.
LI Ke-Bin; CHENG Jing-Tao; WANG Xiao-Fang; ZHOU Ying; LIU Wei-Ping
The application of a mixture of bentazone (3-isopropyl-lH-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide) and atrazine (6-chloro-N2-ethyl-N4-isopropy1-1,3,5-triazine-2,4-diamine) is a practical approach to enhance the herbicidal effect.Labo-ratory incubation experiments were performed to study the degradation of bentazone and atrazine applied in combination and individually in maize rhizosphere and non-rhizosphere soils.After a lag phase,the degradation of each individual herbicide in the non-autoclaved soil could be adequately described using a first-order kinetic equation.During a 30-d in-cubation,in the autoclaved rhizosphere soil,bentazone and atrazine did not noticeably degrade,but in the non-autoclaved soil,they rapidly degraded in both non-rhizosphere and rhizosphere soils with half-lives of 19.9 and 20.2 d for bentazone and 29.1 and 25.7 d for atrazine,respectively.The rhizosphere effect significantly enhanced the degradation of atrazine,but had no significant effect on bentazone.These results indicated that biological degradation accounted for the degrada-tion of both herbicides in the soil.When compared with the degradation of the herbicide applied alone,the degradation rates of the herbicides applied in combination in the soils were lower and the lag phase increased.With the addition of a surfactant,Tween-20,a reduced lag phase of degradation was observed for both herbicides applied in combination.The degradation rate of bentazone accelerated,whereas that of atrazine remained nearly unchanged.Thus,when these two herbicides were used simultaneously,their persistence in the soil was generally prolonged,and the environmental contamination potential increased.
"Heart-cut" bidimensional achiral-chiral liquid chromatography applied to the evaluation of stereoselective metabolism, in vivo biological activity and brain response to chiral drug candidates targeting the central nervous system.
Battisti, Umberto M; Citti, Cinzia; Larini, Martina; Ciccarella, Giuseppe; Stasiak, Natalia; Troisi, Luigino; Braghiroli, Daniela; Parenti, Carlo; Zoli, Michele; Cannazza, Giuseppe
A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug