Exploring the reactivity of bicyclic α-iminophosphonates to access new imidazoline I2 receptor ligands.

[Display omitted] • The bicyclic α-iminophosphonates showed high synthetic possibilities. • Imidazoline I 2 receptors are promising therapeutic targets in neurodegeneration. • (Octahydropyrrolo[3,4- c ]pyrrol-1-yl)phosphonates show affinity/selectivity for imidazoline I 2 receptors. • This is the first time, we showed cognitive improvement in C. elegans after I 2 -IR ligands treatment. Recent studies pointed out the modulation of imidazoline I 2 receptors (I 2 -IR) by selective ligands as a putative strategy to face neurodegenerative diseases. Foregoing the classical 2-imidazoline/imidazole-containing I 2 -IR ligands, we report a family of bicyclic α-iminophosphonates endowed with high affinity and selectivity upon I 2 -IR and we advanced a representative compound B06 in preclinical phases. In this paper, we describe the synthetic possibilities of bicyclic α-iminophosphonates by exploring its ambivalent reactivity, leading to unprecedented molecules that showed promising activities as I 2 -IR ligands in human brain tissues and good BBB permeation capabilities. After in silico ADME prediction studies, we assessed the neuroprotective properties of selected compounds and beneficial effect in an in vitro model of Alzheimeŕs and Parkinson's disease. Along with their neuroprotective effect, compounds showed a potent anti-inflammatory response when evaluated in a neuroinflammation cellular model. Moreover, this is the first time that the neuroprotective effects of imidazoline I 2 -IR ligands in a transgenic Alzheimer's disease Caenorhabditis elegans strain are investigated. Using a thrashing assay, we found a significant cognition improvement in this in vivo model after treatment with the new bicyclic α-phosphoprolines. Therefore, our results confirmed the need of exploring structurally new I 2 -IR ligands and their potential for therapeutic strategies in neurodegeneration. [ABSTRACT FROM AUTHOR]