Exploring the reactivity of bicyclic α-iminophosphonates to access newimidazoline I2 receptor ligands

Abstract

Recent studies pointed out the modulation of imidazoline I2 receptors (I2-IR) by selective ligands as a putativestrategy to face neurodegenerative diseases. Foregoing the classical 2-imidazoline/imidazole-containing I2-IRligands, we report a family of bicyclic α-iminophosphonates endowed with high affinity and selectivity upon I2-IR and we advanced a representative compound B06 in preclinical phases. In this paper, we describe the syntheticpossibilities of bicyclic α-iminophosphonates by exploring its ambivalent reactivity, leading to unprecedentedmolecules that showed promising activities as I2-IR ligands in human brain tissues and good BBBpermeation capabilities. After in silico ADME prediction studies, we assessed the neuroprotective properties ofselected compounds and beneficial effect in an in vitro model of Alzheimeŕs and Parkinson’s disease. Along withtheir neuroprotective effect, compounds showed a potent anti-inflammatory response when evaluated in aneuroinflammation cellular model. Moreover, this is the first time that the neuroprotective effects of imidazolineI2-IR ligands in a transgenic Alzheimer’s disease Caenorhabditis elegans strain are investigated. Using a thrashingassay, we found a significant cognition improvement in this in vivo model after treatment with the new bicyclicα-phosphoprolines. Therefore, our results confirmed the need of exploring structurally new I2-IR ligands andtheir potential for therapeutic strategies in neurodegeneration.