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We report the preparation of novel 1,4,8-triazaphenanthrenes and show that the target compounds are efficiently obtained from the corresponding 6-aminoquinoxalines after N-propargylation followed by copper-catalyzed 6-endo-dig cycloisomerization and aromatization. The cyclization was found to be completely regioselective. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder of aging characterized by motor symptoms that result from the loss of midbrain dopamine neurons and the disruption of dopamine-mediated neurotransmission. There is currently no curative treatment for this disorder. To discover druggable neuroprotective compounds for dopamine neurons, we have designed and synthesized a second-generation of quinoxaline-derived molecules based on structure-activity relationship studies, which led previously to the discovery of our first neuroprotective brain penetrant hit compound MPAQ (5c). Neuroprotection assessment in PD cellular models of our newly synthesized quinoxaline-derived compounds has led to the selection of a better hit compound, PAQ (4c). Extensive in vitro characterization of 4c showed that its neuroprotective action is partially attributable to the activation of reticulum endoplasmic ryanodine receptor channels. Most interestingly, 4c was able to attenuate neurodegeneration in a mouse model of PD, making this compound an interesting drug candidate for the treatment of this disorder. [ABSTRACT FROM AUTHOR]

Background: Deposition of amyloid plaques and neurofibrillary tangles composed of abnormally phosphorylated tau are the neuropathological hallmarks of Alzheimer's disease (AD). However, years before the accumulation of protein aggregates, the abnormal intraneuronal accumulation of heparan sulfates (HS) is observed. This phenomenon breaks a dogma, since HS are classically located on the cell surface and in the extracellular matrix, leading to a new cell autonomous concept in tauopathy, which is the conceptual core of the FET‐OPEN ArrestAD 737390 project. Previously, we provide evidence that inside the cell, HS act as molecular chaperones inducing in Tau conformational changes favoring its abnormal phosphorylation and aggregation (Sepulveda‐Diaz JE. Brain 2015, 138(Pt 5):1339‐54). Thus, molecules able to act on heparan sulfate pathway could represent a new class of compounds for the treatment of AD‐related tauopathies. Method: PAPS is the universal sulfate donor involved in HS biosynthesis and structurally related to ATP. Thus, we first screened kinase inhibitor libraries in a sulfotransferase enzymatic assay (Byrne et al., Biochem. J. 2018; 475:2417‐2433). This strategy, in addition to a HS mimetic, were evaluated for their ability to prevent tauopathy in cells. The best molecules were then evaluated in two transgenic mice model of AD. Thereafter, proof‐of‐concept of the efficacy of compounds selected with this strategy, as well as HS mimetic (Barritault D. Glycoconj J. 2017; 34(3):325‐338) for halting AD‐related tauopathies development was assessed first in vitro and then in vivo. Results: The screening of libraries allowed the identification of 3 hit compounds that, in addition to a HS mimetic, were evaluated for their ability to prevent tauopathy in cells. Two molecules, one HSSTs inhibitor and one heparan sulfate mimetic, were able to reduce tauopathy in cells and in 3xTg‐AD and rTg4510 mouse models of tauopathy. In the in vivo assessment in males and females 3xTg‐AD, the behavioral dose‐response of these molecules on the cognitive, neuropsychiatric‐like and motor AD‐phenotypes was determined. Conclusion: Our results support the FET‐OPEN RIA ArrestAD cell autonomous hypothesis of tauopathy based in altered heparan sulfate biology and place HS and their biosynthetic enzymes as a potential therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a chronic degenerative disorder characterized by typical motor symptoms caused by the death of dopamine (DA) neurons in the midbrain and ensuing shortage of DA in the striatum, at the level of nerve terminals. No curative treatment is presently available for PD in clinical practice. In our search for neuroprotectants in PD, we generated new 1,4,8-triazaphenanthrenes by combining 6-endo-dig-cycloisomerization of propargylquinoxalines and Suzuki or Sonogashira cross-coupling reactions. Neuroprotection assessment of newly synthesized 1,4,8-triazaphenanthrenes in a PD cellular model resulted in the discovery of a new hit compound PPQ (5m). Neuroprotection by 5m was concentration-dependent and the result of a combined effect on intracellular calcium release channels and astroglial cells. Of interest, 5m also counteracted DA cell loss in a mouse model of PD, making this molecule a promising candidate for PD treatment.