Hydrazides as Inhibitors of Histone Deacetylases.

In this Perspective, we have brought together available biological evidence on hydrazides as histone deacetylase inhibitors (HDACis) and as a distinct type of Zn-binding group (ZBG) to be reviewed for the first time in the literature. -Alkyl hydrazides have transformed the field, providing innovative and practical chemical tools for selective and effective inhibition of specific histone deacetylase (HDAC) enzymes, in addition to the usual hydroxamic acid and -aminoanilide ZBG-bearing HDACis. This has enabled efficient targeting of neurodegenerative diseases such as Alzheimer's disease, cancer, cardiovascular diseases, and protozoal pathologies.

Multicomponent Reactions for Multitargeted Compounds for Alzheimer`s Disease.

Alzheimer's Disease (AD) is a multifactorial and fatal neurodegenerative disorder affecting around 35 million people worldwide, which is characterized by decline of cholinergic function, deregulation of amyloid beta (Aβ) oligomers formation and Aβ fibril deposition. Multi-Target- Directed Ligands (MTDLs) have emerged as an original strategy for developing new therapeutic agents on AD. Multicomponent Reactions (MCRs) are a useful alternative to sequential multistep syntheses, allowing scaffold diversity and a rapid and easy access to biologically relevant compounds.

Predicting targets of compounds against neurological diseases using cheminformatic methodology.

Recently developed multi-targeted ligands are novel drug candidates able to interact with monoamine oxidase A and B; acetylcholinesterase and butyrylcholinesterase; or with histamine N-methyltransferase and histamine H3-receptor (H3R). These proteins are drug targets in the treatment of depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease. A probabilistic method, the Parzen-Rosenblatt window approach, was used to build a "predictor" model using data collected from the ChEMBL database.

Exploring the structural basis of the selective inhibition of monoamine oxidase A by dicarbonitrile aminoheterocycles: role of Asn181 and Ile335 validated by spectroscopic and computational studies.

Since cyanide potentiates the inhibitory activity of several monoamine oxidase (MAO) inhibitors, a series of carbonitrile-containing aminoheterocycles was examined to explore the role of nitriles in determining the inhibitory activity against MAO. Dicarbonitrile aminofurans were found to be potent, selective inhibitors against MAO A. The origin of the MAO A selectivity was identified by combining spectroscopic and computational methods.

Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease.

Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC(50) 105 +/- 15 nM) is associated to a 30.

Galanthamine, a natural product for the treatment of Alzheimer's disease.

(-)-Galanthamine is a selective, reversible competitive acetylcholinesterase inhibitor that has been recently approved for the symptomatic treatment of Alzheimer's disease. Galanthamine is a natural product belonging to the Amaryllidaceae family of alkaloids. The pharmacological history of galanthamine shows that the bioactive compound was discovered accidentally in the early 1950s, and the plant extracts were initially used to treat nerve pain and poliomyelitis.