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Human lactate dehydrogenase A (hLDHA) is a homotetrameric isozyme involved in the conversion of glyoxylate into oxalate in the cytosol of liver cells (hepatocytes) and partially responsible for the overproduction of oxalate in patients with the rare disease called primary hyperoxaluria (PH). Recently, hLDHA inhibition has been validated as a safe therapeutic method to try to control the PH disease. Stiripentol (STP) is an approved drug used in the treatment of seizures associated with Dravet's syndrome (a severe form of epilepsy in infancy) which, in addition, has been drawing interest in recent years also for potentially treating PH, due to its hLDHA inhibitory activity. In this work, several new STP-related compounds have been synthesized and their hLDHA inhibitory activity has been compared to that of STP. The synthesis of these analogues to STP was accomplished using crossed-aldol condensation guided by lithium enolate chemistry and a successive regioselective reduction of the resulting α,β-unsaturated ketones. The target molecules were obtained as racemates, which were separated into their enantiomers by chiral HPLC. The absolute configurations of pure enantiomers were determined by the modified Mosher's method and electronic circular dichroism (ECD) spectroscopy. For the inhibitory effect over the hLDHA catalytic activity, a kinetic spectrofluorometric assay was used. All the new synthesized compounds turned out to be more active at 500 μM (46–72% of inhibition percentage) than STP (10%), which opens a new line of study on the possible capacity of these analogues to reduce urinary oxalate levels in vivo more efficiently. [ABSTRACT FROM AUTHOR]

The title compound (1) was obtained within a project to synthesize analogs of the antiepileptic drug stiripentol. Compound 1 was synthesized by aldol addition of the lithium enolate of 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one (2) to 3,3-dimethylbutan-2-one (3), followed by the dehydration of the resulting β-hydroxy-ketone under acid processing. The structure of 1 was established by 1D and 2D NMR spectroscopy and high-resolution mass spectrometry. [ABSTRACT FROM AUTHOR]

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13–18)(a–d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7–12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a–d)) under microwave irradiation at 150–170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 μM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 μM. Additionally, all compounds with IC50 < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 μM, and the other thirteen behaving as double inhibitors. [ABSTRACT FROM AUTHOR]

The Japanese plum tree (Prunus salicina Lindl.) is mainly cultivated in temperate areas of China and some European countries. Certain amounts of wood (from pruning works) are generated every year from this crop of worldwide commercial significance. The main objective of this work was to value this agricultural woody residue, for which the chemical composition of pruning wood extracts from six Japanese plum cultivars was investigated, and the antiproliferative activity of extracts and pure phenolics 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, with the procyanidin (−)-ent-epicatechin-(2α→O→7,4α→8)-epicatechin (5) and the propelargonidin (+)-epiafzelechin-(2β→O→7,4β→8)-epicatechin (7) being the major components of the wood extracts. Some quantitative differences were found among plum cultivars, and the content of proanthocyanidins ranged from 1.50 (cv. 'Fortune') to 4.44 (cv. 'Showtime') mg/g of dry wood. Regarding the antitumoral activity, eight wood extracts and four phenolic compounds were evaluated in MCF-7 cells after 48 h of induction, showing the wood extract from cv. 'Songold' and (‒)-annphenone (3), the best antiproliferative activity (IC50: 424 μg/mL and 405 μg/mL, respectively). [ABSTRACT FROM AUTHOR]

A description of new antimicrobial agents suitable for food industries has become necessary, and natural compounds are being considered as promising sources of new active derivatives to be used with the aim of improving food safety. We have previously described desirable antimicrobial and antibiofilm activities against foodborne bacteria by analogs to A-type proanthocyanidins (PACs) with a nitro (NO2) group at carbon 6 of the A-ring. We report herein the synthesis of eight additional analogs with chloro and bromo atoms at the A-ring and the systematic study of their antimicrobial and antioxidant activities in order to evaluate their possible application as biocides or food preservatives, as well as to elucidate new structure–activity relationships. The results from this study show that halogenated analogs to natural A-type proanthocyanidins rise above the nitro derivatives previously reported in their antimicrobial activities. Gram-positive bacteria are the most sensitive to all the analogs and combinations assayed, showing MICs from 10 to 50 μg/mL in most cases, as well as reductions in biofilm formation and the disruption of preformed biofilms of at least 75%. Some structure–activity relationships previously described have also been corroborated. Analogs with just one OH group at the B-ring show better antimicrobial activities than those with two OH groups, and those analogs with two or three OH groups in the whole structure are more active than those with four OH groups. In addition, the analogs with two OH groups at the B-ring and chloro at the A-ring are the most effective when antibiofilm activities are studied, especially at low concentrations. [ABSTRACT FROM AUTHOR]

Giardiasis is a parasitosis caused by Giardia lamblia with significant epidemiological and clinical importance due to its high prevalence and pathogenicity. The lack of optimal therapies for treating this parasite makes the development of new effective chemical entities an urgent need. In the search for new inhibitors of the adenylyl cyclase gNC1 obtained from G. lamblia, 14 extracts from Argentinian native plants were screened. Lepechinia floribunda and L. meyenii extracts exhibited the highest gNC1 inhibitory activity, with IC50 values of 9 and 31 µg/mL, respectively. In silico studies showed rosmarinic acid, a hydroxycinnamic acid present in both mentioned species, to be a promising anti-gNC1 compound. This result was confirmed experimentally, with rosmarinic acid showing an IC50 value of 10.1 µM. Theoretical and experimental findings elucidate the molecular-level mechanism of rosmarinic acid, pinpointing the key interactions stabilizing the compound–enzyme complex and the binding site. These results strongly support that rosmarinic acid is a promising scaffold for developing novel compounds with inhibitory activity against gNC1, which could serve as potential therapeutic agents to treat giardiasis. [ABSTRACT FROM AUTHOR]

Human lactate dehydrogenase (hLDH) is a tetrameric enzyme present in almost all tissues. Among its five different isoforms, hLDHA and hLDHB are the predominant ones. In the last few years, hLDHA has emerged as a therapeutic target for the treatment of several kinds of disorders, including cancer and primary hyperoxaluria. hLDHA inhibition has been clinically validated as a safe therapeutic method and clinical trials using biotechnological approaches are currently being evaluated. Despite the well-known advantages of pharmacological treatments based on small-molecule drugs, few compounds are currently in preclinical stage. We have recently reported the detection of some 2,8-dioxabicyclo[3.3.1]nonane core derivatives as new hLDHA inhibitors. Here, we extended our work synthesizing a large number of derivatives (42–70) by reaction between flavylium salts (27–35) and several nucleophiles (36–41). Nine 2,8-dioxabicyclo[3.3.1]nonane derivatives showed IC50 values lower than 10 µM against hLDHA and better activity than our previously reported compound 2. In order to know the selectivity of the synthesized compounds against hLDHA, their hLDHB inhibitory activities were also measured. In particular, compounds 58, 62a, 65b, and 68a have shown the lowest IC50 values against hLDHA (3.6–12.0 µM) and the highest selectivity rate (>25). Structure–activity relationships have been deduced. Kinetic studies using a Lineweaver–Burk double-reciprocal plot have indicated that both enantiomers of 68a and 68b behave as noncompetitive inhibitors on hLDHA enzyme. [ABSTRACT FROM AUTHOR]

Sweet cherry (Prunus avium L.) is a tree widely cultivated in temperate regions for its tasty and healing fruits. Pruning works on the tree give each year considerable amounts of woody wastes that hardly have any utility. The aims of this work were to detect the most active antioxidants present in a cherry pruning wood sample, to isolate and characterize them, and study the antimicrobial and antibiofilm activities of components found in the wood ethyl acetate extract against a selection of foodborne microorganisms. The online HPLC–DPPH technique allowed the detection of two active antioxidant peaks that, after being isolated by a combination of countercurrent chromatography (FCPC) and conventional preparative techniques, and subsequent structural characterization by NMR, MS and polarimetry, resulted to be (‒)-catechin (1) and (‒)-taxifolin (4). Other components of the cherry wood extract were also isolated, among which compounds 1, 4, and (+)-dihydrowogonin (12) have never been reported in P. avium. A selection of the isolated flavonoids was submitted to antimicrobial and antibiofilm activity evaluations against strains from type culture collections, as well as on multi-resistant strains previously isolated in our laboratory. Those compounds with antimicrobial activity detected in preliminary screenings by standard agar diffusion tests ‒the flavan-3-ol 1, the flavanonols 4 and (+)-aromadendrin (5), the flavanone (+)-pinocembrin (15), and the flavone tectochrysin (17)‒ were subjected to the minimal inhibitory concentration (MIC) test, showing all of them MIC values of 100 μg/mL. Compound 4 also induced a significative inhibition on the formation of biofilms by Enterobacter sp. UJA37p at a concentration of 1 μg/mL and a significative disruption of preformed biofilm by this strain at 0.1 µg/mL. Similar results on biofilm disruption were observed with compound 17. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the antimicrobial and antibiofilm activities of two procyanidins isolated from an ethyl acetate extract of laurel wood against a selection of foodborne pathogens. The analysis of the extract by HPLC- DAD/ ESI- MS allowed us to detect the presence of two procyanidins, which were selectively isolated and identified by chromatographic and spectroscopic means as cinnamtannin B-1 ( 1) and procyanidin B-2 ( 2). Procyanidins 1 and 2 exhibited two biological activities: inhibition of bacterial growth at high concentrations and prevention of biofilm formation at lower concentrations. Synergistic effect was also detected when both compounds were tested in combination against Listeria monocytogenes. Significant effects were also detected on disruption of preformed biofilm. The ability of procyanidins to inhibit microbial growth and biofilm formation and to synergistically work with each other may stimulate a market as natural food preservatives, and/or natural sanitisers for processing equipment where foodborne pathogens reside. [ABSTRACT FROM AUTHOR]