Thiazolo[5,4-c]isoquinolines: synthesis, functionalization and potential applications

• Autor(a) principal: Costa, Letícia Daniela da Silva
• Data de Publicação: 2024
• Idioma: eng
• Título da fonte: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Texto Completo: http://hdl.handle.net/10773/41652
• topic: Thiazolo[5,4-c]isoquinolines; Thiazolo[5,4-d]thiazoles; Photophysical properties; Biological properties; In-silico calculations; Kinase inhibitors; Acetylcholinesterase inhibitors; Enzymatic assays

The reaction between dithiooxamide and aromatic aldehydes is a well-established procedure for the synthesis of thiazolo[5,4-d]thiazoles (TzTz). However, upon re-examining this reaction, our investigation revealed that employing benzaldehydes with a leaving group at the ortho position, such as an halogen atom or a nitro group, the direction of the reaction may be changed, and a new family of compounds, the thiazolo[5,4-c]isoquinolines (TzIQ), can be obtained. The influence of various factors, including the nature, quantity, and positioning of substituent groups on the chosen benzaldehyde was analyzed, alongside with the impact of the solvent, temperature, and the presence or absence of lanthanum(III) triflate as a catalyst on the reaction's outcome. The TzIQ are a family of heteroaromatic compounds neglected since first synthesized in 1966, probably due to the lack of an easier route for its synthesis. Therefore, little is known about the chemistry, and potential applications of these compounds. The one-step procedure described here allowed us to synthesize a library of “simple” and “mixed” TzIQ. Some of these derivatives were used as valuable intermediates in the synthesis of more elaborated compounds, namely through Suzuki–Miyaura cross-coupling reactions and nucleophilic aromatic substitution reactions. The unequivocal structural elucidation of all synthesized compounds was performed by 1D and 2D nuclear magnetic resonance and mass spectrometry experiments and supported, in some cases, by single-crystal X-ray diffraction studies. The photophysical and biological properties of the prepared compounds were also assessed. A computer-aided drug design (CADD) approach allowed to find out that all studied “simple” TzIQ have a high probability of being acetylcholinesterase (AChE) inhibitors. The computational findings were supported by enzymatic assays against Electrophorus electricus acetylcholinesterase. With the lowest value of IC50 and a behavior very similar to Donepezil®, which is the drug usually used to treat the symptoms associated with the Alzheimer's disease, compound 7b proved to be a good AChE inhibitor and potentially useful as drug. The presence of fluorine atoms the in the TzIQ molecules seems to have a beneficial effect on their enzymatic activity.