Day: November 21, 2022

Hoveyda, Hamid R. published the artcileDiscovery and Optimization of Novel Antagonists to the Human Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part I), HPLC of Formula: 1375066-73-1, the publication is Journal of Medicinal Chemistry (2015), 58(7), 3060-3082, database is CAplus and MEDLINE.

Neurokinin-3 receptor (NK₃R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. The authors therefore decided to explore NK₃R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma LH and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK₃R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogs to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models.

Journal of Medicinal Chemistry published new progress about 1375066-73-1. 1375066-73-1 belongs to thiazole, auxiliary class Thiadiazole,Hydrazine,Amine,Hydrazide,Amide, name is 3-Methyl-1,2,4-thiadiazole-5-carbohydrazide, and the molecular formula is C4H6N4OS, HPLC of Formula: 1375066-73-1.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Noerholm, Ann-Beth published the artcileSynthesis, Pharmacological and Structural Characterization, and Thermodynamic Aspects of GluA2-Positive Allosteric Modulators with a 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide Scaffold, Formula: C10H11FN2O2S, the publication is Journal of Medicinal Chemistry (2013), 56(21), 8736-8745, database is CAplus and MEDLINE.

Pos. 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 receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacol. testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator I in complex with GluA2-LBD-L483Y-N754S was subjected to structural anal. by X-ray crystallog., and the thermodn. of binding was studied by isothermal titration calorimetry. Compound I binds to GluA2-LBD-L483Y-N754S with a K_d of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of pos. allosteric modulator. The major structural factor increasing the binding affinity of I seems to be interactions between the cyclopropyl group of I and the backbone of Phe495 and Met496.

Journal of Medicinal Chemistry published new progress about 1204572-55-3. 1204572-55-3 belongs to thiazole, auxiliary class Neuronal Signaling,GluR, name is 4-Cyclopropyl-7-fluoro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, and the molecular formula is C10H11FN2O2S, Formula: C10H11FN2O2S.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Noerholm, Ann-Beth published the artcileThermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces, Name: 4-Cyclopropyl-7-fluoro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, the publication is Journal of Chemical Information and Modeling (2014), 54(12), 3404-3416, database is CAplus and MEDLINE.

Pos. allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer’s disease. In the present study, the authors describe the synthesis, pharmacol., and thermodn. studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides I [R = 5-F, 6-F, 7-F, 8-F]. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodn. driving forces. Binding of I [R = 7-F] and I [R = H] is enthalpy driven, and I [R = 5-F] and I [R = 6-F] are entropy driven. For I [R = 8-F], both quantities were equal in size. Thermodn. integration (TI) and one-step perturbation (OSP) were used to calculate the relative binding affinity of the modulators. The OSP calculations had a higher predictive power than those from TI, and combined with the shorter total simulation time, the authors found the OSP method to be more effective for this setup. Furthermore, from the mol. dynamics simulations, the authors extracted the enthalpies and entropies, and along with the ITC data, this suggested that the differences in binding free energies are largely explained by the direct ligand-surrounding enthalpies. Furthermore, the authors used the OSP setup to predict binding affinities for a series of polysubstituted fluorine compounds and monosubstituted Me compounds and used these predictions to characterize the modulator binding pocket for this scaffold of pos. allosteric modulators.

Journal of Chemical Information and Modeling published new progress about 1204572-55-3. 1204572-55-3 belongs to thiazole, auxiliary class Neuronal Signaling,GluR, name is 4-Cyclopropyl-7-fluoro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, and the molecular formula is C10H11FN2O2S, Name: 4-Cyclopropyl-7-fluoro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Larsen, Anja Probst published the artcileSynthesis 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, Product Details of C10H11FN2O2S, the publication is ACS Chemical Neuroscience (2016), 7(3), 378-390, database is CAplus and MEDLINE.

Pos. 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 neurol. disorders, for example, Alzheimer’s disease. Here, we report synthesis and pharmacol. evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC_2× = 2.7-4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC_2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural anal. in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure-activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide compounds The Me substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-dioxide (BTD) scaffold. When a Me substituent is present in the 3-position of the BTD, addnl. Me substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency.

ACS Chemical Neuroscience published new progress about 1204572-55-3. 1204572-55-3 belongs to thiazole, auxiliary class Neuronal Signaling,GluR, name is 4-Cyclopropyl-7-fluoro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, and the molecular formula is C10H11FN2O2S, Product Details of C10H11FN2O2S.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Krintel, Christian published the artcileEnthalpy-entropy compensation in the binding of modulators at ionotropic glutamate receptor GluA2, Category: thiazole, the publication is Biophysical Journal (2016), 110(11), 2397-2406, database is CAplus and MEDLINE.

The 1,2,4-benzothiadiazine 1,1-dioxide type of pos. 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 2 neighboring ligand binding domains and act by stabilizing the agonist-bound open-channel conformation. The driving forces behind the binding of these modulators can be significantly altered with only minor substitutions to the parent mols. Here, the authors show that changing the 7-F substituent of modulators BPAM 97 (I) and BPAM 344 (II) into a OH group (BPAM 557 (III) and BPAM 521 (IV), resp.), leads to a more favorable binding enthalpy (ΔH, kcal/mol) from -4.9 for I and -7.5 for II to -6.2 for III and -14.5 for IV, but also a less favorable binding entropy (-TΔS, kcal/mol) from -2.3 for I and -1.3 for II to -0.5 for III and 4.8 for IV. Thus, the dissociation constants (K_d, μM) of III (11.2) and IV (0.16) were similar to those of I (5.6) and II (0.35). Functionally, III and IV potentiated responses of 10 μM L-glutamate at homomeric rat GluA2(Q)_i receptors with EC₅₀ values of 67.3 and 2.45 μM, resp. The binding mode of IV was examined with x-ray crystallog., showing that the only change compared to that of earlier compounds was the orientation of Ser-497 pointing toward the OH group of IV. The favorable enthalpy could be explained by the formation of a H-bond from the side-chain OH group of Ser-497 to the OH group of IV, whereas the unfavorable entropy might be due to desolvation effects combined with a conformational restriction of Ser-497 and IV. In summary, this study shows a remarkable example of enthalpy-entropy compensation in drug development accompanied with a likely explanation of the underlying structural mechanism.

Biophysical Journal published new progress about 1204572-55-3. 1204572-55-3 belongs to thiazole, auxiliary class Neuronal Signaling,GluR, name is 4-Cyclopropyl-7-fluoro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, and the molecular formula is C10H11FN2O2S, Category: thiazole.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Schlegel, Mark K. published the artcileChirality Dependent Potency Enhancement and Structural Impact of Glycol Nucleic Acid Modification on siRNA, Computed Properties of 1192027-04-5, the publication is Journal of the American Chemical Society (2017), 139(25), 8537-8546, database is CAplus and MEDLINE.

Here we report the investigation of glycol nucleic acid (GNA), an acyclic nucleic acid analog, as a modification of siRNA duplexes. We evaluated the impact of (S)- or (R)-GNA nucleotide incorporation on RNA duplex structure by determining three individual crystal structures. These structures indicate that the (S)-nucleotide backbone adopts a conformation that has little impact on the overall duplex structure, while the (R)-nucleotide disrupts the phosphate backbone and hydrogen bonding of an adjacent base pair. In addition, the GNA-T nucleobase adopts a rotated conformation in which the 5-Me group points into the minor groove, rather than the major groove as in a normal Watson-Crick base pair. This observation of reverse Watson-Crick base pairing is further supported by thermal melting anal. of GNA-C and GNA-G containing duplexes where it was demonstrated that a higher thermal stability was associated with isoguanine and isocytosine base pairing, resp., over the canonical nucleobases. Furthermore, it was also shown that GNA nucleotide or dinucleotide incorporation increases resistance against snake venom phosphodiesterase. Consistent with the structural data, modification of an siRNA with (S)-GNA resulted in greater in vitro potencies over identical sequences containing (R)-GNA. A walk of (S)-GNA along the guide and passenger strands of a GalNAc conjugate duplex targeting mouse transthyretin (TTR) indicated that GNA is well tolerated in the seed region of both strands in vitro, resulting in an approx. 2-fold improvement in potency. Finally, these conjugate duplexes modified with GNA were capable of maintaining in vivo potency when s.c. injected into mice.

Journal of the American Chemical Society published new progress about 1192027-04-5. 1192027-04-5 belongs to thiazole, auxiliary class Other Aliphatic Heterocyclic,Amine, name is N,N-Dimethyl-N’-(3-thioxo-3H-1,2,4-dithiazol-5-yl)formimidamide, and the molecular formula is C5H7N3S3, Computed Properties of 1192027-04-5.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Kamber, Markus published the artcileComparison of the Ames II and traditional Ames test responses with respect to mutagenicity, strain specificities, need for metabolism and correlation with rodent carcinogenicity, Formula: C14H12N2S, the publication is Mutagenesis (2009), 24(4), 359-366, database is CAplus and MEDLINE.

The Ames II Salmonella mutagenicity assay procedure was used to test 71 chems., and the results were compared with those from the traditional Ames Salmonella test using the NTP database as the reference All Ames II tests were performed using a fluctuation procedure in microplate format, using TAMix for the detection of base pair substitutions and TA98 to detect frameshift mutations. There was 84% agreement between the two procedures in identifying mutagens and nonmutagens, which is equivalent to the intra- and interlaboratory reproducibility of 87% for the traditional test. The two tests also performed similarly in their predictions of rodent carcinogenicity.

Mutagenesis published new progress about 92-36-4. 92-36-4 belongs to thiazole, auxiliary class Organic Pigment, name is 2-(4-Aminophenyl)-6-methylbenzothiazole, and the molecular formula is C14H12N2S, Formula: C14H12N2S.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Noyce, Donald S. published the artcileTransmission of substituent effects in heterocyclic systems. Rates of solvolysis of substituted thiazolylethanol derivatives, Product Details of C4H5NS2, the publication is Journal of Organic Chemistry (1973), 38(19), 3318-21, database is CAplus.

The rates of solvolysis for several substituted 1-(5-thiazolyl)ethanol derivatives were measured in 80% EtOH and are compared with similar studies on other heterocycles. For the group 1-(2-X-5-thiazolyl)ethyl chlorides, reaction rates are well correlated by σp+ for the substituents X. Similar correlation is observed for the solvolysis rates of 1-(5-X-2-thiazolyl)ethyl chlorides. These results are discussed in terms of the application of MO calculations relevant to the thiazole system.

Journal of Organic Chemistry published new progress about 5053-24-7. 5053-24-7 belongs to thiazole, auxiliary class Thiazole,sulfides, name is 2-(Methylthio)thiazole, and the molecular formula is C4H5NS2, Product Details of C4H5NS2.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Caton-Williams, Julianne published the artcileConvenient synthesis of nucleoside 5′-(α-P-thio)triphosphates and phosphorothioate nucleic acids (DNA and RNA), SDS of cas: 1192027-04-5, the publication is Science China: Chemistry (2012), 55(1), 80-89, database is CAplus.

Modified deoxy- and ribo-nucleoside triphosphates are chem. synthesized in multiple steps due to the protection and deprotection of the nucleoside functionalities. To conveniently synthesize the S-modified triphosphates for enzymically preparing phosphorothioate DNAs and RNAs (PS-DNA and PS-RNA) as potential therapeutics, herein we report a one-pot strategy to synthesize the deoxy- and ribo-nucleoside 5′-(α-P-thio)triphosphates (dNTPαS and NTPαS) without protecting any nucleoside functionalities. This facile synthesis is achieved by treating the nucleosides with a mild phosphitylating reagent, reacting selectively with the 5′-hydroxyl group of each unprotected nucleoside, followed by sulfurization and hydrolysis to afford the crude dNTPαS and NTPαS analogs (mixtures of S_p and R_p diastereomers). We also demonstrated that after just simple precipitation (without HPLC and ion-exchange purification), the quality of the synthesized dNTPαS and NTPαS analogs is excellent for direct DNA polymerization and RNA transcription, resp. Since Klenow DNA polymerase and T7 RNA polymerase accept the S_p diastereomers of dNTPαS and NTPαS analogs, resp., while the R_p diastereomers are neither substrates nor inhibitors, the diastereomerically-pure PS-DNAs and PS-RNAs can be conveniently synthesized enzymically.

Science China: Chemistry published new progress about 1192027-04-5. 1192027-04-5 belongs to thiazole, auxiliary class Other Aliphatic Heterocyclic,Amine, name is N,N-Dimethyl-N’-(3-thioxo-3H-1,2,4-dithiazol-5-yl)formimidamide, and the molecular formula is C5H7N3S3, SDS of cas: 1192027-04-5.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica

Asif, Nida published the artcileBiofabrication and characterization of cyanobacteria derived ZnO NPs for their bioactivity comparison with commercial chemically synthesized nanoparticles, Product Details of C18H24N6O6S4, the publication is Bioorganic Chemistry (2021), 104999, database is CAplus and MEDLINE.

Due to unique properties of the nanoparticles (NPs) with biocompatibility, their application as drug in drug delievery and diagnostics, the recent scientific branch nanotechnol. has emerged as hope in modern medicine. Zinc oxide nanoparticles (ZnO NPs) have gained tremendous interest due to their potential use as chemotherapeutic and antimicrobial agents. They are included in the category of “generally recognized as safe (GRAS) metal oxide”. There is an urgent need for developing addnl. sources of ZnO NPs. Therefore, in the present study 30 cyanobacterial extracts were screened for ZnO NPs synthesis.. The color change of the reaction mixture from blue to pale white indicated the synthesis of ZnO NPs. It was further confirmed by UV-Visible spectroscopy that showed the absorption peak at 372 nm. The SEM anal. during screening revealed that Oscillatoria sp. synthesized smallest ZnO NPs (∼40 nm) that were further optimized for their higher yield by altering reaction conditions (pH, temperature, reaction time, concentration of extract and metal precursor). Best conditions for ZnO NPs synthesis are (0.02 M zinc nitrate, 10 mL of extract volume, pH 8, at 80°C for 3 h). The NPs were purified through calcination at 350°C and characterized by UV-Vis, FTIR, XRD, SEM-EDAX, TEM, Zeta potential and DLS anal. The comparative anal. of purified biogenic ZnO NPs with com. chem. synthesized ZnO NPs (CS), exhibited their superior nature as antioxidant and anti-bacterial agent against both gram-pos. and gram-neg. bacteria. Synergistic effects of biogenic ZnO NPs and streptomycin addnl. favored for their future use as a potential biomedical agent.

Bioorganic Chemistry published new progress about 30931-67-0. 30931-67-0 belongs to thiazole, auxiliary class Salt,Hydrazine,Amine,Benzothiazole, name is Ammonium 2,2′-(hydrazine-1,2-diylidene)bis(3-ethyl-2,3-dihydrobenzo[d]thiazole-6-sulfonate), and the molecular formula is C18H24N6O6S4, Product Details of C18H24N6O6S4.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/thiazole,
Thiazole | chemical compound | Britannica