(2-Imidazolin-4-yl)phosphonates: Green Chemistry and Biology Walk Together

Abstract

2-Imidazoline-containing compounds constitute a valuable class of agents that modulate α2- adrenergic receptors and often show a high affinity for imidazoline I2-receptors (I2-IR). Moreover, 2- imidazolines are an important class of heterocyclic scaffolds found in natural product chemistry, coordination chemistry, and homogeneous catalysis. To meet the demand for 2-imidazolinecontaining compounds, different synthetic approximations were developed. In this work, we describe an efficient and user-friendly synthetic process involving the combination of isocyanidebased multicomponent reaction and microwave heating without the need of anhydrous atmosphere or additional solvents that generates unprecedented (2-imidazolin-4-yl)phosphonates [1]. We assessed the pharmacological profile and selectivity of the prepared compounds upon I2-IR. Owing to the outstanding high I2-IR affinity of one of the prepared compounds and high selectivity devoid to the α2-adrenoceptor of other compounds, markedly better than any described I2-IR ligand to date, (2-imidazolin-4-yl)phosphonates might be considered as a suitable scaffold for designing novel I2-IR ligands [2]. In addition, we demonstrated the effectiveness of two of the new I2-IR ligands in an in vivo female model for cognitive decline (SAMP8), and we analyzed the pathological biomarkers for neurodegeneration. This study is the first experimental evidence that demonstrates the possibility of using this receptor as a target for cognitive impairment [3]. Note, theoretical studies were carried out for designing compounds with enhanced activity and selectivity upon I2-IR based on created 3D-QSAR model. In this work, green chemistry to access an unprecedented scaffold and promising pharmacological results in the neurodegeneration field walked together.