Multiple approaches for developing novel FPR2 Agonists with Pro-Resolving, Anti-Inflammatory, and Antioxidant Properties: Bioisosteres of ureidopropanamide-based agonists, H2S-Releasing Moieties grafting, and Multicomponent Reaction strategies

Neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD), are commonly associated with chronic neuroinflammation and oxidative stress, two interrelated conditions that exacerbate disease progression. In recent years, the resolution of inflammation (RoI) has emerged as a crucial therapeutic target for mitigating these pathological processes. RoI is an active mechanism that transitions the inflammatory response from a pro-inflammatory to a pro-resolving state, restoring tissue homeostasis. This process is mediated by endogenous Specialized Pro-Resolving Mediators (SPMs), including lipoxins, resolvins, and protectins, which activate the G-protein-coupled receptor Formyl Peptide Receptor 2 (FPR2). FPR2, expressed on immune cells, plays a pivotal role in innate immunity, chemotaxis, and tissue repair. Its activation by SPMs or synthetic small-molecule agonists promotes anti-inflammatory and pro-resolving pathways, offering a promising strategy for managing neuroinflammation. In addition to FPR2, the endogenous gasotransmitter hydrogen sulfide (H2S) exhibits significant antioxidant and neuroprotective properties, particularly at low concentrations. Combining FPR2 activation with H2S release represents a novel dual-action approach for addressing the chronic neuroinflammation and oxidative stress that characterize neurodegenerative disorders. Our group has developed a new class of compounds, featuring an ureidopropanamide scaffold, that act as potent and selective FPR2 agonists, showing pro-resolving, anti-inflammatory and neuroprotective activities. Ureiodopropanamide compounds exhibit limitations, such as low aqueous solubility. Therefore, to deeply investigate SAR studies about ureidopropanamide compounds, we employed rational design strategies, including bioisosteric replacement of the ureido group with heteroaromatic rings, squaramides, or indole derivatives. Additionally, we explored multicomponent reactions (MCRs) to develop novel FPR2 agonists featuring innovative moieties that enhance pharmacokinetic and physicochemical properties. Finally, we developed new ureidopropanamide-based derivatives which act as FPR2 agonists and simultaneously release H2S through thioamide or thiourea functionalities. These hybrid molecules were designed to enhance both anti-inflammatory and neuroprotective activities, as demonstrated in preliminary in vitro models of neuroinflammation. Herein, we report the synthesis, computational studies, and preliminary biological evaluation of these new compounds.