Molecular and Crystal Structure of 7,7-Dimethyl-2-pyridin-4-yl-6,7-dihydro-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine [1]

When crystallized from ethanol, 7,7-dimethyl-2-pyridin-4-yl-6,7-dihydro-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine forms crystals which have monoclinic (P21/n) symmetry with unit cell dimensions a = 7.3326(5) Å, b = 19.4897(14) Å, c = 8.6586(6) Å, α = 90°, β = 106.069(2)°, γ = 90°, V = 1189.06(14) Å3, Z = 4. The triazine ring in the molecule has a flattened boat conformation with gem-dimethyl groups as flagpole and bowsprit at the bow. The puckering parameters for the ring are: Q = 0.2996(14) Å, θ = 111.7(3)° and φ = 124.1(3)°. In the crystal, molecules are arranged in the three types of chains generated by the intermolecular NH···N hydrogen bonds. The extended chains with the C(11) graph-set motif running along a [010] axis are formed by the amino group hydrogen atom and the pyridine nitrogen atom of another molecule. The C(4)C(6) chains with the R22(8) binary graph-set motif running along a [101] direction are formed by linking the amino group hydrogen atom and the hydrogen atom at the triazine nitrogen atom with the triazole and triazine nitrogen atoms of another molecule, respectively. The centrosymmetric inverted dimers are formed via the C-H···π interactions between the methyl group hydrogen and the pyridine ring of the pair molecule

7-(4-Fluoro­benzyl­amino)-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine methanol disolvate1

The 1,2,4-triazolo[1,5-a][1,3,5]triazine system in the title compound, C17H14FN7·2CH3OH, is essentially planar, with an r.m.s. deviation of 0.0215 Å. The attached phenyl ring lies almost in the mean plane of the heterocyclic core [dihedral angle = 3.56 (4)°]. In the crystal, centrosymmetric inversion dimers connected via inter­molecular N—H⋯N hydrogen bonds between H atom of the primary amino group and the triazine N atom [R 2 2(8) graph-set motif] form sheets parallel to (010). A second set of dimers connected via N—H⋯F hydrogen bonds between the other H atom of the primary amino group and the F atom forms an R 2 2(24) graph-set motif linking the sheets. Methanol solvent mol­ecules are packed in channels running along the [010] direction

Activation of Caspase-6 Is Promoted by a Mutant Huntingtin Fragment and Blocked by an Allosteric Inhibitor Compound

Aberrant activation of caspase-6 (C6) in the absence of other hallmarks of apoptosis has been demonstrated in cells and tissues from patients with Huntington disease (HD) and animal models. C6 activity correlates with disease progression in patients with HD and the cleavage of mutant huntingtin (mHTT) protein is thought to strongly contribute to disease pathogenesis. Here we show that the mHTT1-586 fragment generated by C6 cleavage interacts with the zymogen form of the enzyme, stabilizing a conformation that contains an active site and is prone to full activation. This shift toward enhanced activity can be prevented by a small-molecule inhibitor that blocks the interaction between C6 and mHTT1-586. Molecular docking studies suggest that the inhibitor binds an allosteric site in the C6 zymogen. The interaction of mHTT1-586 with C6 may therefore promote a self-reinforcing, feedforward cycle of C6 zymogen activation and mHTT cleavage driving HD pathogenesis