Molecular Iodine-Promoted [3 + 2] Oxidative Cyclization for the Synthesis of Heteroarene-Fused [1,2,4] Thiadiazoles/Selenadiazoles
Two new classes of heteroarene-fused [1,2,4]thiadiazole and [1,2,4]selenadiazole are synthesized through the iodine-mediated [3 + 2] oxidative cyclization of 2-aminoheteroarenes and isothiocyanates/isoselenocyanates. This oxidative [3 + 2] annulation stra
Design and synthesis of conformationally constraint Dyrk1A inhibitors by creating an intramolecular H-bond involving a benzothiazole core
We present the development of conformationally pre-organised Dyrk1A inhibitors based on the hydroxybenzothiazole urea scaffold. The modifications introduced to the discovered hit (AHS-211) proved the crucial role of the urea linker to preserve the bioacti
6-Benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17-HSD10 and potential drugs for Alzheimer's disease treatment: Design, synthesis and in vitro evaluation
Background: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17-hydroxysteroid dehydrogenase type 10 (17-HSD10) has been connected with the pathogenesis of Alzheimer's disease (AD). ABAD/17-HSD10 is a binding site for the amyloid-beta peptide (A) inside the mitochondrial matrix where it exacerbates A toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods: As ABAD’s enzymatic activity is required for mediating A toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/17-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structure-activity relationship QSAR and pharmacophore studies have been performed. Results and Conclusion: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40 M) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.