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Much progress has been made in designing analogues that can potentially confer neuroprotection against debilitating neurodegenerative disorders, yet the multifactorial pathogenesis of this cluster of diseases remains a stumbling block for the successful design of an 'ultimate' drug. However, with the growing popularity of the "one drug, multiple targets" paradigm, many researchers have successfully synthesized and evaluated drug-like molecules incorporating a propargylamine function that shows potential to serve as multifunctional drugs or multitarget-directed ligands. It is the aim of this review to highlight the reported activities of these propargylamine derivatives and their prospect to serve as drug candidates for the treatment of neurodegenerative disorders.

Indazoles are heterocyclic moieties rarely found in nature. They are nitrogen containing chemical compounds composed of a pyrazole ring condensed with a benzene ring. Various indazole derivatives have been described with a wide variety of biological activities. This has aroused great interest in the development of novel indazole based therapeutic agents. Areas covered: Forty-two patents published within the last 5 years (2013-2017) describing derivatives with the indazole scaffold and their therapeutic applications were analysed. Expert opinion: The indazole scaffold is of great pharmacological importance as it forms the basic structure of a large number of compounds with potential therapeutic value. Derivatives have been found to possess promising anticancer and anti-inflammatory activity and have also found application in disorders involving protein kinases (aside from cancer) and neurodegeneration. The compounds where mechanism of action is defined can afford new molecules with biological and therapeutic properties.

Polycyclic cage scaffolds have been successfully used in the development of numerous lead compounds demonstrating activity in the central nervous system (CNS). Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and stroke, as well as drug abuse, can be modulated with polycyclic cage derivatives. These cage moieties, including adamantane and pentacycloundecane derivatives, improve the pharmacokinetic and pharmacodynamic properties of conjugated parent drugs and serve as an important scaffold in the design of therapeutically active agents for the treatment of neurological disorders. In this Minireview, we focus on the recent developments in the field of polycyclic cage compounds, as well as the relationship between the lipophilic character of these cage-derived drugs and the ability of such compounds to target and reach the CNS and improve the pharmacodynamic properties of compounds conjugated to it.

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5-(Adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazole (4) was identified as a potential 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor and this paper describes the in-depth structural analysis thereof. Compound 4 was synthesized in a 92% yield and its 3D-structure confirmed by single-crystal X-ray diffraction. Hirshfeld surface analysis indicated that H…H, C-H…C, C-H…Cl and especially C-H…N hydrogen bond interactions are the primary contributors to the intermolecular stabilisation in the crystal. In order to explore the properties of 4, free from the influence of the crystal field, density functional theory (DFT) calculations were conducted. Results indicated that the DFT optimized geometry of 4 produced a conformer (4a) that is significantly different from the crystal structure. Further experiments confirmed that the crystal structure is not the absolute minimum conformation. This indicated that the crystal packing forces has significantly influenced the conformation thereof. Frontier molecular orbital energies and net atomic charges were also calculated to elucidate the electronic properties of 4a. These results provided insight into areas of the molecule that may present with the ability to form binding interactions at the 11β-HSD1 active site. Molecular docking experiments revealed important intermolecular interactions between 4a and 11β-HSD1. These results indicate that 4 may be considered for further drug design endeavors.

The NOS isoforms are attractive targets in drug design for various pathological conditions and have received considerable interest over recent years. With the advances in molecular biology, modeling software, synthesis, bioassays, and our understanding of the NOS enzymes and the function of NO, novel bioavailable and highly selective drug therapies utilizing this mode of action may soon see the light.