Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel hLDHA Inhibitors

Costa, Iván Díaz; Salido, Sofı́a; Nogueras, Manuel; Cobo, Justo

doi:10.3390/ph15070792

Cited by 4 publications

(1 citation statement)

References 70 publications

(95 reference statements)

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“…However, nowadays, several pharmacological strategies are under study for the treatment of PHs [33] . One of them is the direct inhibition of human hepatic isozyme Lactate Dehydrogenase A ( h LDHA), which is in charge of the transformation of glyoxylate into oxalate, by small synthetic molecules [34–38] . In addition, some natural products and plant extracts rich in phenolic compounds (phenylpropanoids, flavonoids and procyanidins) have been studied for their ability to inhibit h LDHA, [39–41] although it is a field still poorly explored.…”

Section: Introductionmentioning

confidence: 99%

Proanthocyanidins in Pruning Wood Extracts of Four European Plum (Prunus domestica L.) Cultivars and Their hLDHA Inhibitory Activity

Ortega-Vidal

Ruiz-Martos

Salido

et al. 2023

Chemistry & Biodiversity

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European plum tree (Prunus domestica L.) is cultivated in many countries for its delicious and nutritive fruit and, accordingly, certain amounts of wood (from pruning works) are generated every year. The main objective of this work was to value this agricultural woody residue, for which the chemical composition of pruning wood extracts from four European plum cultivars was investigated, and the human lactate dehydrogenase A (hLDHA) inhibitory activity of plum wood extracts and pure proanthocyanidins present in those extracts was measured. For the chemical characterization, total phenolic content and DPPH radical‐scavenging assays and HPLC‐DAD/ESI‐MS analyses were performed, the procyanidin (−)‐ent‐epicatechin‐(2α→O→7,4α→8)‐catechin (4), the phenolic glucoside (−)‐annphenone (3) and the flavan‐3‐ol catechin (1) being the major components of the wood extracts. Some quantitative and qualitative differences were found among plum cultivars, and the content of proanthocyanidins ranged from 1.51 (cv. ‘Claudia de Tolosa’) to 8.51 (cv. ‘De la Rosa’) mg g−1 of dry wood. For the hLDHA inhibitory activity, six wood extracts and six proanthocyanidins were evaluated by a UV spectrophotometric assay, compound 4 showing the highest inhibitory activity (IC50 3.2 μM) of this enzyme involved on the excessive production of oxalate in the liver of patients affected by the rare disease Primary Hyperoxaluria.

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Section: Introductionmentioning

confidence: 99%

Proanthocyanidins in Pruning Wood Extracts of Four European Plum (Prunus domestica L.) Cultivars and Their hLDHA Inhibitory Activity

Ortega-Vidal

Ruiz-Martos

Salido

et al. 2023

Chemistry & Biodiversity

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Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents

Vettorazzi,

Díaz,

Angelina

et al. 2024

Bioorganic Chemistry

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Structure simplification of GNE-140 and discovery of a pyridone based analogue as a potential lead for hLDHA inhibitors

Mo,

Luo,

Liu

et al. 2024

Preprint

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In this paper, taking GNE-140, a structurally complicated hLDHA inhibitor, as a lead compound, 19 simple analogues with a pyrimidone, pyranone or pyridone core were designed and conveniently synthesized. Subsequent biological evaluation indicated that although the pyrimidone core had a weak contribution to hLDHA inhibition, compounds with pyranone or pyridone core exhibited better anti-hLDHA activity. Notably, pyridone-bearing compound 1c showed significant selective inhibition of hLDHA (IC50 = 19.5 ± 2.9 µM) over hLDHB (IC50 = 117.6 ± 13.2 µM). Meanwhile, 1c showed inhibition on the lactate production of lung cancer cell A549. Thus, the result of this study indicated 1c is worthy of further study owing to its convenient synthesis and strong selective hLDHA inhibition.

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Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel hLDHA Inhibitors

Cited by 4 publications

References 70 publications

Proanthocyanidins in Pruning Wood Extracts of Four European Plum (Prunus domestica L.) Cultivars and Their hLDHA Inhibitory Activity

Proanthocyanidins in Pruning Wood Extracts of Four European Plum (Prunus domestica L.) Cultivars and Their hLDHA Inhibitory Activity

Second generation of pyrimidin-quinolone hybrids obtained from virtual screening acting as sphingosine kinase 1 inhibitors and potential anticancer agents

Structure simplification of GNE-140 and discovery of a pyridone based analogue as a potential lead for hLDHA inhibitors

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