Both 5-arylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-diones and 3-thioxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-ones are light-Dependent tumor necrosis factor-α antagonists

Voss, Matthew E.; Carter, Percy H.; Tebben, Andrew J.; Scherle, Peggy; Brown, G. K.; Thompson, Lorin A.; Xu, Meizhong; Lo, Yvonne C.; Yang, Gengjie; Liu, Rui‐Qin; Strzemienski, Paul; Everlof, John G.; Trzaskos, James M.; Decicco, Carl P.

doi:10.1016/s0960-894x(02)00941-1

Cited by 63 publications

(21 citation statements)

References 10 publications

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“…67 Some PAINS are light dependent and react with otherwise unreactive amino acids like the main chain of alanine. 68,69 Compound stability in buffer can also produce misleading time-dependent behavior. 59 It can be difficult to predict the sensitivity of a target protein to these nonspecific reactive events.…”

Section: Identification Of Covalent Inhibitorsmentioning

confidence: 99%

A Perspective on the Kinetics of Covalent and Irreversible Inhibition

2017

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The clinical and commercial success of covalent drugs has prompted a renewed and more deliberate pursuit of covalent and irreversible mechanisms within drug discovery. A covalent mechanism can produce potent inhibition in a biochemical, cellular, or in vivo setting. In many cases, teams choose to focus on the consequences of the covalent event, defined by an IC value. In a biochemical assay, the IC may simply reflect the target protein concentration in the assay. What has received less attention is the importance of the rate of covalent modification, defined by k/K. The k/K is a rate constant describing the efficiency of covalent bond formation resulting from the potency (K) of the first reversible binding event and the maximum potential rate (k) of inactivation. In this perspective, it is proposed that the k/K should be employed as a critical parameter to identify covalent inhibitors, interpret structure-activity relationships (SARs), translate activity from biochemical assays to the cell, and more accurately define selectivity. It is also proposed that a physiologically relevant k/K and an (unbound) AUC generated from a pharmacokinetic profile reflecting direct exposure of the inhibitor to the target protein are two critical determinants of in vivo covalent occupancy. A simple equation is presented to define this relationship and improve the interpretation of covalent and irreversible kinetics.

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Section: Identification Of Covalent Inhibitorsmentioning

confidence: 99%

A Perspective on the Kinetics of Covalent and Irreversible Inhibition

2017

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“…Direct-targeted antivirals typically display morepromising initial toxicity profiles, but the quest for broad-spectrum inhibitory activity has fueled the rediscovery of many promiscuous, often covalently reactive scaffolds that are associated with unclear mechanisms of activity (20)(21)(22)(23). Based on their demonstrated history of ultimate failure in development, many of these scaffolds are considered undesirable and were classified as frequently hitting pan-assay interfering (PAIN) substances (21,24). As a notable exception, different ribonucleoside analogs have been identified, which combine good clinical promise with a broadened indication spectrum, often showing a remarkable preference for a range of viral over host cell polymerases.…”

mentioning

confidence: 99%

Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses

Yoon

Toots

Lee

et al. 2018

Antimicrob Agents Chemother

189

207

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Morbidity and mortality resulting from influenza-like disease are a threat, especially for older adults. To improve case management, next-generation broad-spectrum antiviral therapeutics that are efficacious against major drivers of influenza-like disease, including influenza viruses and respiratory syncytial virus (RSV), are urgently needed. Using a dual-pathogen high-throughput screening protocol for influenza A virus (IAV) and RSV inhibitors, we have identified -hydroxycytidine (NHC) as a potent inhibitor of RSV, influenza B viruses, and IAVs of human, avian, and swine origins. Biochemical polymerase assays and viral RNA sequencing revealed that the ribonucleotide analog is incorporated into nascent viral RNAs in place of cytidine, increasing the frequency of viral mutagenesis. Viral passaging in cell culture in the presence of an inhibitor did not induce robust resistance. Pharmacokinetic profiling demonstrated dose-dependent oral bioavailability of 36 to 56%, sustained levels of the active 5'-triphosphate anabolite in primary human airway cells and mouse lung tissue, and good tolerability after extended dosing at 800 mg/kg of body weight/day. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAVs in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burdens in a guinea pig transmission model and suppressed virus spread to uninfected contact animals through direct transmission. Based on its broad-spectrum efficacy and pharmacokinetic properties, NHC is a promising candidate for future clinical development as a treatment option for influenza-like diseases.

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“…The 2-thioxo-imidazolidine-4-one moiety is also present in our newly synthesized compound and the sulfur analog of hydantoin, in which one carbonyl group is substituted by a thiocarbonyl group [39]. Thioxoimidazolidine derivatives show anticancer, anti-inflammatory, and antiviral activities in Figure 2 [40][41][42][43][44].…”

Section: Introductionmentioning

confidence: 97%

Synthesis of Isatin Derivatives Using Silver Nanoparticles as Green Catalyst: Study of Molecular Docking Interactions in SARS-CoV-2 3c-Like Protease and Determination of Cytotoxic Activities of the Compounds

Packialakshmi

Gobinath

Vijayakumar³

et al. 2021

Journal of Nanomaterials

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The coronavirus disease (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As isatin-containing compounds exhibit several remarkable biological activities, isatin derivatives were prepared to combat the global pandemic caused by SARS-CoV-2 that is gripping the world. Herein, the synthesis of novel isatin derivatives has been reported. The cytotoxic activities of the compounds were determined using cancer cell (MCF-7) and normal cell (MCF-10A and MRC-5) lines. In silico molecular docking experiments were conducted using AutoDock Vina. We have successfully predicted the binding energies and the number of hydrogen bonds present. We have also identified the residues involved in hydrogen bond formation. The target compounds were synthesized using Schiff base following cyclization and Knoevenagel condensation reactions. We have focused on the recyclable synthesis of silver nanoparticles (AgNPs) using the extracts obtained from Dipteryx odorata. The extracts were used to reduce silver ions for the production of AgNPs. The synthesized nanoparticles exhibited excellent catalytic activities during the synthesis of isatin derivatives in ethanol. The formation of the target isatin derivatives has been confirmed using the Fourier transform-infrared (FT-IR), proton nuclear magnetic resonance (1H NMR) spectroscopy, 13C NMR spectroscopy, mass spectrometry, and elemental analysis techniques. Compound 3e was found to be the most active compound when tested against the MCF-7 cancer cell line ( I C 50 = 20.5 μ M ). The activity was comparable to the activities of standard doxorubicin and other compounds. In silico molecular docking experiments were conducted to study the spike protein in SARS-CoV-2 (PDB ID: 6LU7). Compound 3c exhibited high binding ability (−9.4 kcal/mol). The inhibition ability was studied using hydroxychloroquine as a standard. Results from docking studies revealed that the inhibition ability of compound 3c was higher than the inhibition abilities exhibited by other compounds. The synthesized compound 3e is a potential antiviral drug that can be used for treating the COVID-19 disease.

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Both 5-arylidene-2-thioxodihydropyrimidine-4,6(1H,5H)-diones and 3-thioxo-2,3-dihydro-1H-imidazo[1,5-a]indol-1-ones are light-Dependent tumor necrosis factor-α antagonists

Cited by 63 publications

References 10 publications

A Perspective on the Kinetics of Covalent and Irreversible Inhibition

A Perspective on the Kinetics of Covalent and Irreversible Inhibition

Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses

Synthesis of Isatin Derivatives Using Silver Nanoparticles as Green Catalyst: Study of Molecular Docking Interactions in SARS-CoV-2 3c-Like Protease and Determination of Cytotoxic Activities of the Compounds

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