The neurotropic protozoan Toxoplasma gondii is the 2nd leading cause of death due to foodborne illness in the US, and has been designated as one of five neglected parasitic infections by the Center for Disease Control and Prevention. Currently, no treatment options exist for the chronic dormant-phase Toxoplasma infection in the central nervous system (CNS). T. gondii cathepsin L (TgCPL) has recently been implicated as a novel viable target for the treatment of chronic toxoplasmosis. In this study, we report the first body of SAR work aimed at developing potent inhibitors of TgCPL with selectivity vs the human cathepsin L. Starting from a known inhibitor of human cathepsin L, and guided by structure-based design, we were able to modulate the selectivity for Toxoplasma vs human CPL by nearly 50-fold while modifying physiochemical properties to be more favorable for metabolic stability and CNS penetrance. The overall potency of our inhibitors towards TgCPL was improved from 2 μM to as low as 110 nM and we successfully demonstrated that an optimized analog 18b is capable of crossing the BBB (0.5 brain/plasma). This work is an important first step toward development of a CNS-penetrant probe to validate TgCPL as a feasible target for the treatment of chronic toxoplasmosis.

Parkinson's disease (PD) is a neurodegenerative disorder that affects adult people whose treatment is palliative. Thus, we decided to test three dammarane triterpenes 1 , 1a , 1b , and we determined that 1 and 1a inhibit β-aggregation through thioflavine T rather than 1b . Since compound 1 was most active, we determined the interaction between α-synuclein and 1 at 50 µM (Kd) through microscale thermophoresis. Also, we observed differences in height and diameter of aggregates, and α-synuclein remains unfolded in the presence of 1 . Also, aggregates treated with 1 do not provoke neurites' retraction in N2a cells previously induced by retinoic acid. Finally, we studied the potential sites of interaction between 1 with α-synuclein fibrils using molecular modelling. Docking experiments suggest that 1 preferably interact with the site 2 of α-synuclein through hydrogen bonds with residues Y39 and T44.

In the design of self-assembled compounds, small variations in the linkers connecting the coordinating moieties can produce large differences in the obtained structures. Here, we report three novel zinc(II) complexes with phenanthroline-derived ligands as building blocks (L 1 −L 3 ): A mononuclear complex, a bimetallic helicate, and a trimetallic circular helicate. The evennumber spacer in L 2 promotes the formation of a bimetallic helicate stabilized by π-π interactions of adjacent phenanthrolines. The addition of an extra methylene in L 3 increases the distance between where the phenanthrolines can stack, and CH-π noncovalent interactions give stability to the circular helicate. When irradiated at 308 nm in acetonitrile, long-lived excited states are formed with all three complexes, which are able to participate in oxidation of 2-propanol and in reduction of methylviologen, MV 2+ . While the overall behavior of the three complexes is similar, the bimetallic helicate is able to form a ground-state adduct with MV 2+ , while the trimer reaches the excited state to form an exciplex with MV 2+ .

No abstract