Abstract A copper-catalyzed, one-pot, three-component C–H activation reaction of isocyanides, sulfinate salts, and benzothiazole, benzoxazole, or benzimidazole has been developed for the preparation a series of novel functionalized benzazoles bearing a sulfonyl-imine skeleton. This method provides an efficient route to form novel functionalized benzazole derivatives from simple and affordable starting materials under mild reaction conditions in moderate to good yields. Finally, by employing this method, 15 new compounds were synthesized and characterized simply, rapidly, and efficiently (76–92%).
Ethyl 2-methyl-3-(phenylimino)acrylates containing a ketenimine structure are synthesized via the Horner-Wadsworth-Emmons reaction of ethyl 2-(diethylphosphono)propionate and various phenyl isocyanates using potassium hexamethyldisilazide. The synthesis of several 3-iminoacrylic esters and their analogues, all belonging to the class of conjugated ketenimines, is also achieved.
A series of pyrazolo[1,5- a ][1,3,5]triazine derivatives is synthesized and characterized to assess their anticancer potential. Among the tested compounds, 2-(dichloromethyl)-7-(4-methylphenyl)-4-(pyridin-3-yl)pyrazole[1,5- a ][1,3,5]triazine ( 4 ) and its analogue 2-(dichloromethyl)-7-phenyl-4-pyridin-3-ylpyrazolo[1,5- a ][1,3,5]triazine ( 7 ) showed the highest activity. In contrast to the other derivatives, which displayed only weak growth-inhibitory effects, compounds 4 and 7 contain a 3-pyridyl substituent at the C4 position of the pyrazolotriazine scaffold. Both compounds demonstrated broad-spectrum antiproliferative activity in the NCI-60 human cancer cell line panel. Compound 4 exhibited GI (50) values of 0.32-2.22 mu M, with the highest potency against NSCLC, breast cancer, and leukemia cell lines. Compound 7 was even more potent, showing GI (50) values of 0.03-3.04 mu M and selective activity against renal cancer, breast cancer, and leukemia cell lines. In most cases, LC (50) values exceeded 100 mu M, indicating low overall cytotoxicity despite strong growth inhibition. ADMET predictions suggested favorable drug-like properties, including high intestinal absorption, CNS permeability, weak P-gp substrate behavior, and probable P-gp inhibition. Structure-activity relationship (SAR) analysis identified the 2-dichloromethyl group as a key determinant of activity, while the C4 substituent effect followed the order 3-pyridyl > 2-methylphenyl approximate to 2-fluorophenyl > phenyl approximate to 4- tert -butyl.
The sirtuin 1 (SIRT1) enzyme plays a pivotal role in regulating cellular homeostasis, making it a high-priority target for treating abolic and age-related diseases. We report the synthesis and biological evaluation of a novel series of 1,5-benzodiazepine derivatives designed as potential SIRT1 activators. High-throughput screening using recombinant SIRT1 protein in a luminescent assay was employed, identifying 2,4-disubstituted 2,3-dihydro-1H-1,5-benzodiazepines as superior activators, whereas coumarin chalcones inhibit SIRT1 activity. Using molecular docking against hSIRT1, we found that the activators fit perfectly within a hydrophobic pocket of the allosteric site, being anchored by a conventional hydrogen bond to Asn226 and stabilized by it-alkyl interactions with Ile227. Beyond these structural studies, we evaluated the antidiabetic potential of one of the derivatives, known as pyrabentin. The effectiveness of pyrabentin under 8-week oral administration at 100 mg/kg per os in reducing glucose intolerance, insulin resistance, and obesity in animals with the metabolic memory model at the level of action of the comparator drug metformin has been proven. Finally, our findings demonstrate that the heterocyclic substitutions of the 1,5-benzodiazepine moiety are critical determinants of their interaction with the STAC-binding domain, providing a structure-based rationale for more efficient SIRT1 activators for the treatment of type 2 diabetes.
A Pd/C catalyst, prepared by decomposition of tris(diben-zylideneacetone)dipalladium(0) (Pd-2(dba)(3)) on activated carbon (5% Pd), was found to efficiently catalyze the hydrogenation reaction of diene carboxylates featuring isolated saturated ring scaffolds. Under 100 atm H2 at 30 degrees C for 24 h in MeOH, this Pd/C catalyst provided significantly higher yields of the fully saturated products than other tested Pd/C catalysts, particularly for the less reactive five-membered-ring diene substrate. In contrast, hydrogenation of a more reactive six-membered diene proceeded to give high conversion with all catalysts. All catalysts studied showed diminished activity in AcOH (requiring higher Pd loadings for comparable conversion), and very low yields in hexane or THF (consistent with the low H-2 solubility in these solvents). We believe that the proposed Pd/C nanocomposite could be especially beneficial for the hydrogenation of low-reactivity organic compounds, especially for accessing functionalized sp(3)-enriched bicyclic scaffolds.
