Discovery of novel benzothiophene derivatives as potent and narrow spectrum inhibitors of DYRK1A and DYRK1B.

The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.

Novel capsaicin analogues as potential anticancer agents: synthesis, biological evaluation, and in silico approach.

A novel class of benzo[d][1,3]dioxol-5-ylmethyl alkyl/aryl amide and ester analogues of capsaicin were designed, synthesized, and evaluated for their cytotoxic activity against human and murine cancer cell lines (B16F10, SK-MEL-28, NCI-H1299, NCI-H460, SK-BR-3, and MDA-MB-231) and human lung fibroblasts (MRC-5). Three compounds (5f, 6c, and 6e) selectively inhibited the growth of aggressive cancer cells in the micromolar (µM) range. Furthermore, an exploratory data analysis pointed at the topological and electronic molecular properties as responsible for the discrimination process regarding the set of investigated compounds. The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and esters as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents.

N-[(1,3-Benzodioxol-5-yl)meth-yl]-4-methyl-benzamide: an analogue of capsaicin.

In the title compound, C16H15NO3, the five-membered 1,3-dioxole ring is in an envelope conformation with the methyl-ene C atom as the flap atom [lying 0.202 (3) Šout of the plane formed by the other four atoms]. The benzene ring makes a dihedral angle of 84.65 (4)° with the best least-squares plane through the 1,3-benzodioxole fused-ring system, which substitutes the 2-methoxyphenol moiety in capsaicin. In the crystal, mol-ecules are connected into a zigzag supra-molecular chain along the c-axis direction by N-H⋯O hydrogen bonds. These chains are connected into a layer in the ac plane by C-H⋯π inter-actions.

N-[(1,3-Benzodioxol-5-yl)meth-yl]benzene-sulfonamide: an analogue of capsaicin.

The title compound, C14H13NO4S, an analogue of capsaicin, differs from the latter by having a 1,3-benzodioxole ring rather than a 2-meth-oxy-phenol moiety, and having a benzene-sulfonamide group instead of an aliphatic amide chain. The five-membered ring is in an envelope conformation with the methyl-ene C atom lying 0.221 (6) Šout of the plane formed by the other four atoms. The dihedral angle between the phenyl ring and the mean plane of the 1,3-benzodioxole fused-ring system is 84.65 (4)°. In the crystal, mol-ecules aggregate into supra-molecular layers in the ac plane through C-H⋯O, N-H⋯O and C-H⋯π inter-actions.