FDA-Approved Oximes and Their Significance in Medicinal Chemistry

Dhuguru, Jyothi; Zviagin, Ievgen M.; Skouta, Rachid

doi:10.3390/ph15010066

Cited by 49 publications

(37 citation statements)

References 116 publications

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“…Oximes are an established class of pharmaceuticals, with several FDA-approved oxime-based therapeutics used as antidotes for organophosphate poisoning, as well as in cephalosporin antibiotics . In addition, oximes and NO are biologically active in plants, serving functions facilitating plant defense, communication, and growth. ,, While the pathways involved in NO signaling in response to stress are still largely unknown, NO has been shown to regulate gene expression and hormonal activity, as well as provide protection under oxidative stress by interacting with reactive oxygen species .…”

Section: Discussionmentioning

confidence: 99%

C-Diazeniumdiolate Graminine in the Siderophore Gramibactin Is Photoreactive and Originates from Arginine

et al. 2022

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Siderophores are synthesized by microbes to facilitate iron acquisition required for growth. Catecholate, hydroxamate, and α-hydroxycarboxylate groups comprise well-established ligands coordinating Fe(III) in siderophores. Recently, a C-type diazeniumdiolate ligand in the newly identified amino acid graminine (Gra) was found in the siderophore gramibactin (Gbt) produced by Paraburkholderia graminis DSM 17151. The N−N bond in the diazeniumdiolate is a distinguishing feature of Gra, yet the origin and reactivity of this C-type diazeniumdiolate group has remained elusive until now. Here, we identify L-arginine as the direct precursor to L-Gra through the isotopic labeling of L-Arg, L-ornithine, and L-citrulline. Furthermore, these isotopic labeling studies establish that the N−N bond in Gra must be formed between the N δ and N ω of the guanidinium group in L-Arg. We also show the diazeniumdiolate groups in apo-Gbt are photoreactive, with loss of nitric oxide (NO) and H + from each D-Gra yielding E/Z oxime isomers in the photoproduct. With the loss of Gbt's ability to chelate Fe(III) upon exposure to UV light, our results hint at this siderophore playing a larger ecological role. Not only are NO and oximes important in plant biology for communication and defense, but so too are NO-releasing compounds and oximes attractive in medicinal applications. Articles pubs.acs.org/acschemicalbiology

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Section: Discussionmentioning

confidence: 99%

C-Diazeniumdiolate Graminine in the Siderophore Gramibactin Is Photoreactive and Originates from Arginine

et al. 2022

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“…The result of such an interaction is the formation of the free enzyme and phosphylated oxime. Pyridine-2-aldoxime (2-PAM) is the only reactivator of AChE approved by the FDA (US Food and Drug Administration), which is most commonly used to treat OP poisoning compared with other oximes (obidoxime, HI-6) [11,12]. Nevertheless, 2-PAM shows a low degree of phosphylated AChE reactivation in the CNS due to limited ability to cross the blood-brain barrier (BBB).…”

Section: Introductionmentioning

confidence: 99%

Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes

et al. 2022

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Chitosan-decorated liposomes were proposed for the first time for the intranasal delivery of acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) to the brain as a therapy for organophosphorus compounds (OPs) poisoning. Firstly, the chitosome composition based on phospholipids, cholesterol, chitosans (Cs) of different molecular weights, and its arginine derivative was developed and optimized. The use of the polymer modification led to an increase in the encapsulation efficiency toward rhodamine B (RhB; ~85%) and 2-PAM (~60%) by 20% compared to conventional liposomes. The formation of monodispersed and stable nanosized particles with a hydrodynamic diameter of up to 130 nm was shown using dynamic light scattering. The addition of the polymers recharged the liposome surface (from −15 mV to +20 mV), which demonstrates the successful deposition of Cs on the vesicles. In vitro spectrophotometric analysis showed a slow release of substrates (RhB and 2-PAM) from the nanocontainers, while the concentration and Cs type did not significantly affect the chitosome permeability. Flow cytometry and fluorescence microscopy qualitatively and quantitatively demonstrated the penetration of the developed chitosomes into normal Chang liver and M-HeLa cervical cancer cells. At the final stage, the ability of the formulated 2-PAM to reactivate brain AChE was assessed in a model of paraoxon-induced poisoning in an in vivo test. Intranasal administration of 2-PAM-containing chitosomes allows it to reach the degree of enzyme reactivation up to 35 ± 4%.

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“…Heterocyclic compounds and, in particular, nitrogen bearing compounds have tremendous values in the field of medicinal chemistry. With a plethora of potential pharmacological activities, nitrogen containing derivatives continue to enthrall scientists worldwide with their therapeutic properties, and this is the reason why heterocyclic compounds are the building blocks of many drugs and pharmaceutical products [ 4 , 5 , 6 , 7 ]. Among the nitrogen containing heterocyclic aromatic scaffolds, quinazolines are considered as privileged compounds.…”

Section: History and Significance Of Quinazolinesmentioning

confidence: 99%

Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents

Dhuguru

Ghoneim

2022

Molecules

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Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear to outsmart and evade almost any method of treatment by developing drug resistance. Quinazolines are the most versatile, ubiquitous and privileged nitrogen bearing heterocyclic compounds with a wide array of biological and pharmacological applications. Most of the anti-cancer agents featuring quinazoline pharmacophore have shown promising therapeutic activity. Therefore, extensive research is underway to explore the potential of these privileged scaffolds. In this context, a molecular hybridization approach to develop hybrid drugs has become a popular tool in the field of drug discovery, especially after witnessing the successful results during the past decade. Histone deacetylases (HDACs) have emerged as an important anti-cancer target in the recent years given its role in cellular growth, gene regulation, and metabolism. Dual inhibitors, especially based on HDAC in particular, have become the center stage of current cancer drug development. Given the growing significance of dual HDAC inhibitors, in this review, we intend to compile the development of quinazoline based HDAC dual inhibitors as anti-cancer agents.

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FDA-Approved Oximes and Their Significance in Medicinal Chemistry

Cited by 49 publications

References 116 publications

C-Diazeniumdiolate Graminine in the Siderophore Gramibactin Is Photoreactive and Originates from Arginine

C-Diazeniumdiolate Graminine in the Siderophore Gramibactin Is Photoreactive and Originates from Arginine

Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes

Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents

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