ABSTRACT
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 ß-amyloid (Aß) aggregation assay gave further experimental support to this finding: Aß1-40 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 ring-open 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 ring-closed 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.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Models, Molecular , Photosensitizing Agents/pharmacology , Protein Aggregates/drug effects , Animals , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antitubercular Agents/chemistry , Bacterial Proteins/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Light , Mycobacterium tuberculosis/enzymology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Histidine/biosynthesis , Isomerism , Molecular Dynamics Simulation , Photochemistry , Protein Binding , Protein Structure, Secondary , Tryptophan/biosynthesisABSTRACT
Functionalised photoswitches--photochromic dithienylcyclohexenes--were prepared in two steps by a cobalt-mediated Diels-Alder reaction of internal alkynes with the isoprenylpinacolboronic ester. The three-component one-pot reaction sequence provides the photochromic dithienylcyclohexenes in up to 67% overall yield.
