Expanding the DAD9‐Pegasus Scaffold: Synthesis and Functional Evaluation of Sulfur‐Containing Dopamine–Tetracycline Conjugates for Parkinson's Disease

Parkinson's disease (PD) is driven by a combination of dopaminergic neuron loss, α-synuclein (α-Syn) aggregation, and oxidative stress, underscoring the need for multi-target therapies. We previously developed Pegasus (DAD9), a dopamine-doxycycline conjugate designed to couple dopaminergic activity with the neuroprotective properties of tetracyclines while limiting dopamine's oxidative reactivity. In this study, we explore a critical but less-examined element of this scaffold: the linker. By incorporating a sulfur atom and progressively extending the tether, we introduced subtle modifications to modulate molecular flexibility, electronic properties, and physicochemical parameters without disrupting the main pharmacophoric domains. The synthesis of these highly functionalized hybrids required a tailored strategy, highlighting the inherent challenges of working with such complex conjugates. Across the series, all compounds retained their ability to interfere with α-Syn aggregation, showed no effect on cell viability, and lacked antibacterial activity. While modest variations in physicochemical properties were observed, anti-aggregative potency remained comparable across the linker-modified series. Together, these results indicate that the scaffold tolerates linker modification within the explored chemical space, supporting a role for the linker as a modulatory element rather than a primary driver of the main α-Syn-related functional activity.