The Isoxazole Ring and Its N‐Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics

Abstract

Mental disorders are neuropsychiatric conditions that are marked by unusual or irregular thinking, feelings, or behavior, and lead to distress and/or impaired functions. Major psychiatric conditions are depression, anxiety, and psychoses of various types. Their etiopathogeneses, of a primary or secondary origin, are associated with genetic and environmental factors. They are commonly treated with psychoactive drugs (also known as psychotropics), which target serotonin, dopamine, norepinephrine, glutamate, and nuclear receptors (NRs), including retinoic acid receptor-related orphan receptors (RORs) and other receptors in the central nervous system (CNS). Herein we present a diverse array of isoxazole derivatives, among which are some prominent marketed drugs. Some of the derivatives and forms, including N-oxides, are under either (pre)clinical evaluation or patent protection as new generation of psychotropics, and a few have effective blood-brain barrier (BBB) permeability. Various drug-like isoxazol(in)es and their structural features and efficiency, modified through scaffold hopping, are described and discussed in the context of treating neuropsychiatric conditions.

Ring Distortion Diversity‐Oriented Approach to Fully Substituted Furoxans and Isoxazoles

“…Isoxazole motif is a common subunit of many medications, such as flucloxacillin, valdecoxib, and leflunomide. [16] 1,2,5-Oxadiazole 2-oxides (furoxans) are regarded emergent scaffolds with strong application potential in various areas. Furoxans are exogenous donors of nitric oxide (NO), [17] which is a crucial gaseous signaling molecule that mediates various physiological processes and may be useful for cancer treatment.…”

“…One of the important subclasses of heterocyclic pharmaceutical ingredients is the isoxazole family which along with the isoxazole ring itself includes 1,2,4‐ and 1,2,5‐oxadiazole ring systems. Isoxazole motif is a common subunit of many medications, such as flucloxacillin, valdecoxib, and leflunomide [16] . 1,2,5‐Oxadiazole 2‐oxides (furoxans) are regarded emergent scaffolds with strong application potential in various areas.…”

Regioselective Synthesis of Functionalized 3- or 5-Fluoroalkyl Isoxazoles and Pyrazoles from Fluoroalkyl Ynones and Binucleophiles

“…The importance of isoxazoles and pyrazoles for the discovery of new therapeutics and agricultural ingredients was highlighted in a number of reviews. − Because of the advantageous capability of fluorinated substituents to modulate drug-related properties, − their incorporation into azoles provides promising opportunity for drug discovery. For example, substitution of tert- butyl group at the isoxazole ring of BRAF V600E inhibitor 1 to its fluorinated analogue in 3 prevented the metabolic oxidation of 1 to significantly less active derivative 2 (Figure A) and led to the discovery of clinical candidate Agerafenib.…”

Oxazole and Isoxazole Chemistry in Crop Protection

“…The process in preparative investigations on oxazoles , isoxazoles , oxazolines , isoxazolines , oxazolidines , isoxazolidines , oxazolones , isoxazolones , benzoxazoles , and benzisoxazoles has been summarized in exhaustive reviews. Also, the application of most of these heterocyclic scaffolds in medicinal chemistry has been reviewed recently, just to mention the broad pharmacological (e.g., anticancer, antimicrobial, antidiabetic, anti‐inflammatory, and anticonvulsant) activity of benzoxazoles or the specific significance of isoxazoles for neuropsychiatric therapeutics . The only heterocyclic scaffolds, for which so far extensive reviews exist regarding their significance in crop protection chemistry, are pyrazole , thiazole , isothiazole , pyridine , pyridazine , and pyrimidine .…”