Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl-(AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved "photoswitchable". The AChE-induced β-amyloid (Aβ) aggregation assay gave further experimental support to this finding: Aβ 1−40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ringopen and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ringclosed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays.

Controlling the activity of sirtuins is of high biomedical relevance as the enzymes are involved in cancer, neurodegeneration and other diseases.

The activity of the metabolic branch-point enzyme PriA from Mycobacterium tuberculosis (mtPriA) can be controlled reversibly by light. Two-pronged inhibitors based on the dithienylethene scaffold were designed utilizing mtPriA's natural rotational symmetry. Switching from the flexible, ring-open to the rigid, ring-closed isomer reduces inhibition activity by one order of magnitude.

Photochromic dithienylmaleimides are well known molecular switches, but for applications the suitable functionalization of the photochromic scaffold is required. We report here synthetic routes to dithienylmaleimides, which are functionalized at three different positions: at each of the thiophene moieties and the maleimide nitrogen. A Perkin-type condensation of two thiophene precursors is used as the key step to assemble the maleimide core, which a llows the synthesis of non-symmetrically substituted dithienylmaleimides, such as photochromic amino acids. A different approach to the maleimide core is provided by the reaction of a dithienylmaleic anhydride with amines or hydrazides leading to maleimide protected dithienylmaleimides and photochromic labeled natural amino acids. The photochromic properties of the new photoswitches were investigated showing reversible photochromism in polar organic solvents. Results and discussion Synthesis

Die Aktivität des metabolischen Schlüsselenzyms PriA aus Mycobacterium tuberculosis (mtPriA) kann reversibel durch Licht kontrolliert werden. Auf der Grundlage des Dithienylethen-Gerüsts wurden entsprechend der zweifachen Rotationssymmetrie des Proteins symmetrische Inhibitoren mit terminalen Ankern entworfen. Durch Schalten vom flexiblen, offenen Isomer zur starren, geschlossenen Form wurde die Inhibitionsaktivität um eine Grçßenordnung reduziert. Hintergrundinformationen zu diesem Beitrag sind im WWW unter http://dx.doi.org/10.1002/ange.201307207 zu finden.