10.1021/ja806062g.s002 Cristina Rodríguez-Rodríguez Cristina Rodríguez-Rodríguez Natalia Sánchez de Groot Natalia Sánchez de Groot Albert Rimola Albert Rimola Ángel Álvarez-Larena Ángel Álvarez-Larena Vega Lloveras Vega Lloveras José Vidal-Gancedo José Vidal-Gancedo Salvador Ventura Salvador Ventura Josep Vendrell Josep Vendrell Mariona Sodupe Mariona Sodupe Pilar González-Duarte Pilar González-Duarte Design, Selection, and Characterization of Thioflavin-Based Intercalation Compounds with Metal Chelating Properties for Application in Alzheimer’s Disease American Chemical Society 2009 BM compound HBT ligand derivative solution β aggregation studies HBX HBTI hydroxyphenyl metal chelating properties BMI Alzheimer Metal Chelating Properties Zn UV multifunctional ML 2 complexes Cu fluorescence microscopy studies agent HBXI amyloid fibril buildup formation constants 2009-02-04 00:00:00 Dataset https://acs.figshare.com/articles/dataset/Design_Selection_and_Characterization_of_Thioflavin_Based_Intercalation_Compounds_with_Metal_Chelating_Properties_for_Application_in_Alzheimer_s_Disease/2881348 Metal chelation is considered a rational therapeutic approach for interdicting Alzheimer’s amyloid pathogenesis. At present, enhancing the targeting and efficacy of metal-ion chelating agents through ligand design is a main strategy in the development of the next generation of metal chelators. Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules that contain both amyloid binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework (<b>M1</b>), include potential antioxidant properties, facilitate the formation of iodine-labeled derivatives, and can be permeable through the blood−brain barrier. Iodination reactions of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (<b>HBX</b>), 2-(2-hydroxyphenyl)benzothiazole (<b>HBT</b>), and 2-(2-aminophenyl)-1<i>H</i>-benzimidazole (<b>BM</b>), have led to the corresponding iodinated derivatives <b>HBXI</b>, <b>HBTI</b>, and <b>BMI</b>, which have been characterized by X-ray diffraction. The chelating properties of the latter compounds toward Cu(II) and Zn(II) have been examined in the solid phase and in solution. The acidity constants of <b>HBXI</b>, <b>HBTI</b>, and <b>BMI</b> and the formation constants of the corresponding ML and ML<sub>2</sub> complexes [M = Cu(II), Zn(II)] have been determined by UV−vis pH titrations. The calculated values for the overall formation constants for the ML<sub>2</sub> complexes indicate the suitability of the <b>HBXI</b>, <b>HBTI</b>, and <b>BMI</b> ligands for sequestering Cu(II) and Zn(II) metal ions present in freshly prepared solutions of β-amyloid (Aβ) peptide. This was confirmed by Aβ aggregation studies showing that these compounds are able to arrest the metal-promoted increase in amyloid fibril buildup. The fluorescence features of <b>HBX</b>, <b>HBT</b>, <b>BM</b>, and the corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pregrown fibrils, have shown that <b>HBX</b> and <b>HBT</b> compounds could behave as potential markers for the presence of amyloid fibrils, whereas <b>HBXI</b> and <b>HBTI</b> may be especially suitable for radioisotopic detection of Aβ deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimer’s disease therapeutics.