Heterocyclic N-Oxides - An Emerging Class of Therapeutic Agents

Mfuh, Adelphe; Larionov, Oleg V.

doi:10.2174/0929867322666150619104007

Cited by 130 publications

(81 citation statements)

References 209 publications

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“…We then choose to test a subclass of nitroxy compounds for their capacity to inhibit this interaction. Nitroxy compounds have recently emerged as a privileged scaffold for applications in drug discovery 15, 16 . In particular, 1,2-oxazines represent a new structural framework with significant potential for structure diversification.…”

Section: Introductionmentioning

confidence: 99%

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Doens

Valiente

Mfuh³

et al. 2017

ACS Chem. Neurosci.

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Neuroinflammation is one of the hallmarks of Alzheimer's disease pathology. Amyloid β has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid β by microglia depends on the expression of several receptors implicated in the clearance of amyloid and in cell activation. CD36 receptor expressed on microglia interacts with fibrils of amyloid inducing the release of pro-inflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid β compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid β to CD36. We have found 7 molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid β. Molecular docking simulations have suggested the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as a target of these compounds. These molecules also inhibited the production of TNF-α, IL-6 and IL-1β by peritoneal macrophages stimulated with fibrils of amyloid β. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Doens

Valiente

Mfuh³

et al. 2017

ACS Chem. Neurosci.

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“…These impressive achievements have had as ound impact on the drug discovery and developmentp rocess over the past two decades or so, whereas more promising changesa re to be expected in the near future.T he world of microbes and marine organismsw ill be an alternative valuable source of natural products and drug candidates in the years to come. [126,143] [139,140] The isoxazole ring, in ad iverse array of derivatives, will and shouldm ost probablyb eamajor player in both campaigns, amongt he structurest ob ed eveloped as therapeutics for psychiatric conditions and practice, in the years ahead.…”

Section: Discussionmentioning

confidence: 99%

“…[126] The NÀOd ipole of various heterocyclic N-oxides can act as an itric oxide (NO) agonist. They are found either as core units in compoundso fbiological interest, or they serve as versatile synthetic intermediates.N -Oxidation entered mainstream drug discovery,c redited with an improvement of properties and therapeutic outcome.…”

Section: The N-oxide Of Isoxazol(in)ementioning

confidence: 99%

“…They are found either as core units in compoundso fbiological interest, or they serve as versatile synthetic intermediates.N -Oxidation entered mainstream drug discovery,c redited with an improvement of properties and therapeutic outcome. [126] The NÀOd ipole of various heterocyclic N-oxides can act as an itric oxide (NO) agonist. Some heterocyclic N-oxides, such as furoxans, are known as masked NO donors, liberating NO under thiol mediation.…”

Section: The N-oxide Of Isoxazol(in)ementioning

confidence: 99%

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

et al. 2017

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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.

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“…[2] In fact, the chemistry and applications of aromatic N-oxides have been receiving increased attention over the last two decades due to their usefulness as potential anticancer, antibacterial, antihypertensive, antiparasitic, anti-HIV, anti-inflammatory, herbicidal, neuro-protective, and procognitive agents. [3,4] ArNÀOX are useful as protecting groups, auxiliary agents, oxidants, ligands in metal complexes, and catalysts. [5] Also, ArNÀOX have been shown to be useful in energetic materials applications such as propellants, explosives, and pyrotechnics.…”

Section: Introductionmentioning

confidence: 99%

A Biocatalytic Synthesis of HeteroaromaticN‐Oxides by Whole Cells ofEscherichia coliExpressing the Multicomponent, Soluble Di‐Iron Monooxygenase (SDIMO) PmlABCDEF

et al. 2019

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Aromatic N-oxides (ArNÀOX) are desirable biologically active compounds with a potential for application in pharmacy and agriculture industries. As biocatalysis is making a great impact in organic synthesis, there is still a lack of efficient and convenient enzyme-based techniques for the production of aromatic N-oxides. In this study, a recombinant soluble di-iron monooxygenase (SDIMO) PmlABCDEF overexpressed in Escherichia coli was showed to produce various aromatic N-oxides. Out of 98 tested Nheterocycles, seventy were converted to the corresponding N-oxides without any side oxidation products. This whole-cell biocatalyst showed a high activity towards pyridines, pyrazines, and pyrimidines. It was also capable of oxidizing bulky N-heterocycles with two or even three aromatic rings. Being entirely biocatalytic, our approach provides an environmentally friendly and mild method for the production of aromatic N-oxides avoiding the use of strong oxidants, organometallic catalysts, undesirable solvents, or other environment unfriendly reagents.

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Heterocyclic N-Oxides - An Emerging Class of Therapeutic Agents

Cited by 130 publications

References 209 publications

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

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

A Biocatalytic Synthesis of HeteroaromaticN‐Oxides by Whole Cells ofEscherichia coliExpressing the Multicomponent, Soluble Di‐Iron Monooxygenase (SDIMO) PmlABCDEF

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