Abstract
6-Bromochromone-2-carboxylic acid (3) was synthesized by a microwave-assisted process. The optimization of the reaction was performed varying parameters, such as type of base/number of reagent equivalents, solvent, temperature and reaction time. The yield of the reaction was improved to 87%. The new synthetic route is versatile as several chromone-2-carboxylic acids (compounds 4B–10B) were obtained with good yields (54–93%). Only in the case of the nitro substituent (compound 11B), an ester was obtained instead of the desired carboxylic acid. Following this synthetic route chromone carboxylic acids can be attained with a high degree of purity, without the need of the tedious and expensive purification processes through column chromatography. The reaction is safe, cost-effective, fast and robust, and can be used in the development of concise and diversity-oriented libraries based on chromone scaffold. The overall study can be looked as a step forward to speed-up the discovery of chromone-based multitarget-directed ligands.
Highlights
Chromones are oxygen-containing heterocyclic compounds with a benzoannelated γ-pyrone ring widely distributed in nature and present in notable amounts in several species [1,2]
As the chromone is commercially available it was used as standard allowing a rapid confirmation of its formation along the reaction by thin-layer chromatography (TLC)
6-bromochromone-2-carboxylic was carried outsynthesis using 5′-bromo-2′4-oxo-4H-chromene-2-carboxylic acid derivatives in order to obtain the suitable synthons to speed-up hydroxyacetophenone (1) as starting material and reaction conditions similar to the classic reaction the progress on the discovery described in the literature
Summary
Chromones are oxygen-containing heterocyclic compounds with a benzoannelated γ-pyrone ring widely distributed in nature and present in notable amounts in several species [1,2]. They are well-known by their diversity of pharmacological properties, such as antiallergic, anti-inflammatory, antidiabetic, antitumor, and antimicrobial [2]. Chromone (4H-chromen-4-one; 4H-1-benzopyran-4-one) is a privileged structure used in drug discovery programs, being the scaffold recognized as a pharmacophore of a great number of bioactive molecules [1,2,3] As neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, are characterized as multifactorial pathologies, the development of multitarget-directed ligands is a hot drug discovery issue [4]. In this context, following a multitarget strategy, our research group have developed chromone-based multitarget ligands as bifunctional acetylcholinesterase (AChE) and monoamine oxidase (MAO) inhibitors (Figure 1) [5].
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