Identification of N-acylhydrazone derivatives as novel lactate dehydrogenase A inhibitors

Rupiani, Sebastiano; Buonfiglio, Rosa; Manerba, Marcella; Ianni, Lorenza Di; Vettraino, Marina; Giacomini, Elisa; Masetti, Matteo; Falchi, Federico; Stefano, Giuseppina Di; Roberti, Marinella; Recanatini, Maurizio

doi:10.1016/j.ejmech.2015.06.028

Cited by 26 publications

(14 citation statements)

References 37 publications

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“…Similarly, copper complexes of other hydrazones have a higher antimicrobial action than their parent ligands, when used against tuberculosis for example [13,16]. The various compounds containing a hydrazide side chain or their derivatives exhibit anticancer activity [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

The complexing properties of oxalodihydrazide, acethydrazide and formic hydrazide with Cu(II) in aqueous solution

Woźniczka

Szajdzińska‐Piętek

Jezierska

et al. 2017

Inorganica Chimica Acta

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Section: Introductionmentioning

confidence: 99%

The complexing properties of oxalodihydrazide, acethydrazide and formic hydrazide with Cu(II) in aqueous solution

Woźniczka

Szajdzińska‐Piętek

Jezierska

et al. 2017

Inorganica Chimica Acta

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“…The inhibitory activity of the pyrimidine-quinolone hybrids 10 , 15 , 19, and 24 – 31 ( a – c ) against the h LDHA enzyme was measured by a kinetic spectrofluorometric assay [ 66 ].…”

Section: Resultsmentioning

confidence: 99%

“…h LDHA activity was determined throughout a fluorometric method with pyruvate as substrate and NADH co-factor, as previously reported [ 66 , 68 , 69 ] and modified as described here: in each well, the final volume was set to 200 µL, and the final concentrations were 100 mM potassium phosphate buffer, 0.041 units/mL h LDHA (95%, specific activity >300 units/mg and concentration of 0.5 mg/mL, Abcam, Cambridge, United Kingdom), 151 µM β-NADH, 1 mM pyruvate (saturated conditions), and DMSO solutions (2%, v / v ) of pure compounds at concentrations in the range of 0.048–100 µM. The reaction was initiated by the addition of pyruvate, and the NADH concentration decrease was measured for 10 min in a TECAN Infinite 200 Pro M Plex fluorescence plate reader at 28 °C, with excitation at 340 nm and emission at 460 nm.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A (hLDHA) inhibitors. Structures with different linkers between the pyrimidine and quinolone scaffolds (10-21 and 24–31) were studied in silico, and those with the 2-aminophenylsulfide (U-shaped) and 4-aminophenylsulfide linkers (24–31) were finally selected. These new pyrimidine-quinolone hybrids (24–31)(a–c) were easily synthesized in good to excellent yields by a green catalyst-free microwave-assisted aromatic nucleophilic substitution reaction between 3-(((2/4-aminophenyl)thio)methyl)quinolin-2(1H)-ones 22/23(a–c) and 4-aryl-2-chloropyrimidines (1–4). The inhibitory activity against hLDHA of the synthesized hybrids was evaluated, resulting IC50 values of the U-shaped hybrids 24–27(a–c) much better than the ones of the 1,4-linked hybrids 28–31(a–c). From these results, a preliminary structure–activity relationship (SAR) was established, which enabled the design of novel 1,3-linked pyrimidine-quinolone hybrids (33–36)(a–c). Compounds 35(a–c), the most promising ones, were synthesized and evaluated, fitting the experimental results with the predictions from docking analysis. In this way, we obtained novel pyrimidine-quinolone hybrids (25a, 25b, and 35a) with good IC50 values (<20 μM) and developed a preliminary SAR.

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“…The therapeutic interest for LDH inhibition prompted the development of potent, dual or selective, active-site LDH inhibitors. [24][25][26][27][28][29][30] However, despite intense efforts, pharmacological LDH inhibition struggled to translate to in vivo activity. 27,29,31,32 In fact, LDHs are usually recognized as poorly druggable targets, and different reasons can account for this.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides

Thabault

Liberelle

Koruza

et al. 2021

Journal of Biological Chemistry

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Identification of N-acylhydrazone derivatives as novel lactate dehydrogenase A inhibitors

Cited by 26 publications

References 37 publications

The complexing properties of oxalodihydrazide, acethydrazide and formic hydrazide with Cu(II) in aqueous solution

The complexing properties of oxalodihydrazide, acethydrazide and formic hydrazide with Cu(II) in aqueous solution

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

Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides

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