Antithyroid agents and QSAR studies: inhibition of lactoperoxidase-catalyzed iodination reaction by isochromene-1-thiones

Kirthana, M. V.; Khan, Fazlur-Rahman Nawaz; Sivakumar, Ponnurengam Malliappan; Doble, Mukesh; Manivel, P.; Prabakaran, K.; Krishnakumar, Varadhan

doi:10.1007/s00044-013-0475-x

Cited by 4 publications

(2 citation statements)

References 45 publications

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“…Ideally future use of this assay would substitute human recombinant TPO enzyme. Another more immediate solution could be use of lactoperoxidase instead of TPO, which has been used previously as a surrogate for TPO, although the specificity of this approach would require further evaluation (Divi and Doerge, 1994;Doerge and Niemczura, 1989;Kirthana et al, 2013;Taurog et al, 1996). In addition to addressing ethical concerns regarding animal use for toxicology studies, eliminating reliance on animal thyroid tissue might also improve assay transferability to laboratories without access to a vivarium and trained necropsy technicians.…”

Section: Discussionmentioning

confidence: 99%

Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries

et al. 2016

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High-throughput screening for potential thyroid-disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the U.S. Environmental Protection Agency ToxCast screening assay portfolio. To fill 1 critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast phase I and II chemical libraries, comprised of 1074 unique chemicals, were initially screened using a single, high concentration to identify potential TPO inhibitors. Chemicals positive in the single-concentration screen were retested in concentration-response. Due to high false-positive rates typically observed with loss-of-signal assays such as AUR-TPO, we also employed 2 additional assays in parallel to identify possible sources of nonspecific assay signal loss, enabling stratification of roughly 300 putative TPO inhibitors based upon selective AUR-TPO activity. A cell-free luciferase inhibition assay was used to identify nonspecific enzyme inhibition among the putative TPO inhibitors, and a cytotoxicity assay using a human cell line was used to estimate the cellular tolerance limit. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO and an orthogonal peroxidase oxidation assay using guaiacol as a substrate to confirm the activity profiles of putative TPO inhibitors. This effort represents the most extensive TPO inhibition screening campaign to date and illustrates a tiered screening approach that focuses resources, maximizes assay throughput, and reduces animal use.

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Section: Discussionmentioning

confidence: 99%

Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries

et al. 2016

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“…In addition, these molecules are the most important and largely used zinc binding function for the design of CA isoenzymes inhibitors. It was highlighted that the sulfonamide groups are an ideal ligand for some enzyme active site [ 52 , 53 ].…”

Section: Resultsmentioning

confidence: 99%

Secondary Sulfonamides as Effective Lactoperoxidase Inhibitors

et al. 2017

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Secondary sulfonamides (4a–8h) incorporating acetoxybenzamide, triacetoxybenzamide, hydroxybenzamide, and trihydroxybenzamide and possessing thiazole, pyrimidine, pyridine, isoxazole and thiadiazole groups were synthesized. Lactoperoxidase (LPO, E.C.1.11.1.7), as a natural antibacterial agent, is a peroxidase enzyme secreted from salivary, mammary, and other mucosal glands. In the present study, the in vitro inhibitory effects of some secondary sulfonamide derivatives (4a–8h) were examined against LPO. The obtained results reveal that secondary sulfonamide derivatives (4a–8h) are effective LPO inhibitors. The Ki values of secondary sulfonamide derivatives (4a–8h) were found in the range of 1.096 × 10−3 to 1203.83 µM against LPO. However, the most effective inhibition was found for N-(sulfathiazole)-3,4,5-triacetoxybenzamide (6a), with Ki values of 1.096 × 10−3 ± 0.471 × 10−3 µM as non-competitive inhibition.

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Montmorillonite-KSF-catalyzed synthesis of 4-heteroarylidene-N-arylhomophthalimides by Knoevenagel condensation

et al. 2014

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Antithyroid agents and QSAR studies: inhibition of lactoperoxidase-catalyzed iodination reaction by isochromene-1-thiones

Cited by 4 publications

References 45 publications

Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries

Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries

Secondary Sulfonamides as Effective Lactoperoxidase Inhibitors

Montmorillonite-KSF-catalyzed synthesis of 4-heteroarylidene-N-arylhomophthalimides by Knoevenagel condensation

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