No abstract

The initial transition of amyloid beta (1-42) (Abeta42) soluble monomers/small oligomers from unordered/alpha-helix to a beta-sheet-rich conformation represents a suitable target to design new potent inhibitors and to obtain effective therapeutics for Alzheimer's disease. Under optimized conditions, this reliable and reproducible CD kinetic study showed a three-step sigmoid profile that was characterized by a lag phase (prevailing unordered/alpha-helix conformation), an exponential growth phase (increasing beta-sheet secondary structure) and a plateau phase (prevailing beta-sheet secondary structure). This kinetic analysis brought insight into the inhibitors' mechanism of action. In fact, an increase in the duration of the lag phase can be related to the formation of an inhibitor-Abeta complex, in which the non-amyloidogenic conformation is stabilized. When the exponential rate is affected exclusively, such as in the case of Congo red and tetracycline, then the inhibitor affinity might be higher for the pleated beta-sheet structure. Finally, by adding the inhibitor at the end of the exponential phase, the soluble protofibrils can be disrupted and the Abeta amyloidogenic structure can revert into monomers/small oligomers. Congo red and tetracycline preferentially bind to amyloid in the beta-sheet conformation because both decreased the slope of the exponential growth, even if to a different extent, whereas no effect was observed for tacrine and galantamine. Some very preliminary indications can be derived about the structural requirements for binding to nonamyloidogenic or beta-sheet amyloid secondary structure for the development of potent antiaggregating agents. On these premises, memoquin, a multifunctional molecule that was designed to become a drug candidate for the treatment of Alzheimer's disease, was investigated under the reported circular dichroism assay and its anti-amyloidogenic mechanism of action was elucidated.

In Table 1, the word "Trihexyphenidyl" is misspelled and the structures given for L-dopa and Piribedil are incorrect. The correct structures for these compounds are shown below.

The coupling of two different pharmacophores, each endowed with different biological properties, afforded the hybrid compound lipocrine (7), whose biological profile was markedly improved relative to those of prototypes tacrine and lipoic acid. Lipocrine is the first compound that inhibits the catalytic activity of AChE and AChE-induced amyloid-beta aggregation and protects against reactive oxygen species. Thus, it emerged as a valuable pharmacological tool to investigate Alzheimer's disease and as a promising lead compound for new anti-Alzheimer drugs.

A design strategy to convert a dual-binding site AChE inhibitor into triple functional compounds with promising in vitro profile against multifactorial syndromes, such as Alzheimer's disease, is proposed. The lead compound bis(7)-tacrine (2) was properly modified to confer to the new molecules the ability of chelating metals, involved in the neurodegenerative process. The multifunctional compounds show activity against human AChE, are able to inhibit the AChE-induced amyloid-beta aggregation, and chelate metals, such as iron and copper.

To date, the pharmacotherapy of Alzheimer's disease (AD) has relied on acetylcholinesterase (AChE) inhibitors (AChEIs) and, more recently, an N-methyl-D-aspartate receptor (NMDAR) antagonist. AD is a multifactorial syndrome with several target proteins contributing to its etiology. "Multi-target-directed ligands" (MTDLs) have great potential for treating complex diseases such as AD because they can interact with multiple targets. The design of compounds that can hit more than one specific AD target thus represents an innovative strategy for AD treatment. Tacrine was the first AChEI introduced in therapy. Recent studies have demonstrated its ability to interact with different AD targets. Furthermore, numerous tacrine homo- and heterodimers have been developed with the aim of improving and enlarging its biological profile beyond its ability to act as an AChEI. Several tacrine hybrid derivatives have been designed and synthesized with the same goal. This review will focus on and summarize the last two years of research into the development of tacrine derivatives able to hit AD targets beyond simple AChE inhibition.

Redox impairment is a prominent feature of Alzheimer's disease (AD). It has led to the "oxidative stress hypothesis", which proposes antioxidants as beneficial therapeutic tools in AD treatment. To date, a wide variety of antioxidants have been examined as neuroprotectants. However, success has been elusive in clinical trials. Several factors have contributed to this failure, including the complexity of the redox system in vivo. Potentially critical aspects include the fine-tuned equilibrium between antioxidant defenses and free radical production, the lack of specific antioxidant target(s), and the inherent difficulty in delivering antioxidants where they are needed. Herein, we highlight significant progress in the field. Future directions of antioxidant research are also presented.

Hoffen auf Heilung: Memoquin (1) beeinflusst einige Mechanismen der Alzheimer‐Krankheit: die Bildung reaktiver Sauerstoffspezies, die Umwandlung und Aggregation von Amyloid‐β(Aβ)‐Peptiden und die Acetylcholinesterase‐Aktivität. Im Tierversuch wurde mit 1 die Bildung neurodegenerativer Merkmale deutlich unterdrückt, und die Verhaltensstörungen gingen merklich zurück. Die Enzyme hAChE, BACE‐1 und NQO1 werden von 1 adressiert.