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Propynylidene derivatives of dimethyl malonate and Meldrumʼs acid, as well as cross-conjugated enynones, containing Me3Si, Et3Si, and t-BuMe2Si groups reacted with 4-methyl-, 4-methoxy-, and 4-chloro-benzenethiol under basic conditions to give the corresponding addition products with buta-1,3-diene and penta-1,4-dien-3-one fragments with high stereoselectivity. The thiylation products of enyne derivatives of dimethyl malonate and Meldrumʼs acid retain the trialkylsilyl group, whereas the addition of benzenethiols to 5-(tri-alkylsilyl)-1-phenylpent-1-en-4-yn-3-ones is accompanied by desilylation. Some mechanistic features of the described reactions have been established, and methods for the stereoselective synthesis of sulfur-containing polyunsaturated compounds have been developed. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI), often experienced at the intensive care units, is associated with high morbidity/mortality where ischemia-reperfusion injury is a main causative factor. Succinate accumulation during ischemia contributes to the excessive generation of reactive oxygen species at reperfusion. Inhibition of succinate dehydrogenase has been associated with protective outcome in cardiac ischemia-reperfusion after 24h, but the effects on kidney and mitochondrial functions are less well studied. Aim: To investigate the therapeutic potential of succinate dehydrogenase inhibition, by using dimethyl malonate (DMM), on kidney and mitochondria functions in a mouse model of AKI. Methods: Male C57BL/6J mice were pre-treated with DMM or placebo, i.p. 30min prior to bilateral renal ischemia (20min). After 3-days of reperfusion, glomerular filtration rate (GFR) was calculated from plasma clearance of FITC-inulin. Kidney mitochondria was isolated and mass specific and intrinsic mitochondrial function were evaluated by high resolution respirometry. Kidney sections were stained (i.e., hematoxylin-eosin and TUNEL) and analyzed for histopathological evaluation of injuries and apotosis, respectively. NADPH oxidase activity in kidney and human proximal tubular cell-line (HK2) were measured luminometrically. Results: DMM treatment improved GFR (p

Microglia activation drives the pro-inflammatory activity in the early stages of Alzheimer's disease (AD). However, the mechanistic basis is elusive, and the hypothesis of targeting microglia to prevent AD onset is little explored. Here, we demonstrated that upon LPS exposure, microglia shift towards an energetic phenotype characterised by high glycolysis and high mitochondrial respiration with dysfunction. Although the activity of electron transport chain (ETC) complexes is boosted by LPS, this is mostly devoted to the generation of reactive oxygen species. We showed that by inhibiting succinate dehydrogenase (SDH) with dimethyl malonate (DMM), it is possible to modulate the LPS-induced metabolic rewiring, facilitating an anti-inflammatory phenotype. DMM improves mitochondrial function in a direct way and by reducing LPS-induced mitochondrial biogenesis. Moreover, the block of SDH with DMM inhibits the recruitment of hypoxia inducible-factor 1 α (HIF-1α), which mediates the induction of glycolysis and cytokine expression. Similar bioenergetic alterations were observed in the microglia isolated from AD mice (3xTg-AD), which present high levels of circulating LPS and brain toll-like receptor4 (TLR4). Moreover, this well-established model of AD was used to show a potential effect of SDH inhibition in vivo as DMM administration abrogated brain inflammation and modulated the microglia metabolic alterations of 3xTg-AD mice. The RNA-sequencing analysis from a public dataset confirmed the consistent transcription of genes encoding for ETC subunits in the microglia of AD mice (5xFAD). In conclusion, TLR4 activation promotes metabolic changes and the pro-inflammatory activity in microglia, and SDH might represent a promising therapeutic target to prevent AD development.

The intermolecular hydrogen bond interactions in the dimethyl malonate with some branched alkanols (2-methyl-1-propanol, 2-propanol, and 2-butanol) binary mixture have been studied experimentally and theoretically. The ultrasonic velocities U, densities ρ of binary mixtures of dimethyl malonate with 2-methyl-1-propanol, 2-propanol, 2-butanol from 303.15 K to 318.15 K were measured. Excess molar volume (VE), deviation in adiabatic compressibility (δβad) and excess intermolecular free length (LEf) have been calculated from the measured experimental data. It is observed that the order of interactions in dimethyl malonate - branched alkanols mixtures is 2-methyl-1-propanol > 2-propanol > 2-butanol. [ABSTRACT FROM AUTHOR]

• Facile solvent-free synthesis of levoglucosenone-derived Michael adducts with dimethyl malonate. • Reaction carried out in a microwave oven for times as short as 2 min. • Acids and bases catalyst screening resulted in CaO as the best performing catalyst. Among biomass-derived platform molecules one of the most prominent structures is levoglucosenone (LGO) from which it is possible to derive a wide array of solvents, chemicals, and polymeric materials. In this work we investigated the Michael addition of dimethyl malonate on levoglucosenone by testing several alternative catalysts ranging from Lewis acids to structured silicas and clays. The work had the double aim to i) optimize the reaction using the widely reported KF/Alumina catalyst, giving a frame of reference for its relative activity in this Michael addition and ii) conduct a catalyst screen while investigating various reaction mechanisms. Among the tested catalysts, Ca(OH) 2 was the best candidate to substitute KF/Alumina, reaching yields >90 % after only 5 min of microwave irradiation. [Display omitted] [ABSTRACT FROM AUTHOR]

Dimethyl sulfoxide (DMSO) is widely used as a solvent in organic synthesis and in pharmacology because of its low cost, stability, and non-toxicity. Multicomponent reactions are a powerful synthetic tool for the rapid and efficient construction of complicated molecular frameworks. In this communication, the multicomponent transformation of salicylaldehyde, malononitrile dimer, and dimethyl malonate in DMSO at room temperature was carefully investigated to give dimethyl 2-(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-5-yl)malonate with good yield. The structure of the new compound was established by means of elemental analysis and mass, nuclear magnetic resonance, and infrared spectroscopy. [ABSTRACT FROM AUTHOR]

Dimethyl sulfoxide (DMSO) is widely used as a solvent in organic synthesis and in pharmacology because of its low cost, stability, and non-toxicity. Multicomponent reactions are a powerful synthetic tool for the rapid and efficient construction of complicated molecular frameworks. In this communication, the multicomponent transformation of salicylaldehyde, malononitrile dimer, and dimethyl malonate in DMSO at room temperature was carefully investigated to give dimethyl 2-(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-5-yl)malonate with good yield. The structure of the new compound was established by means of elemental analysis and mass, nuclear magnetic resonance, and infrared spectroscopy.

Monocytes (Mos) are crucial in the evolution of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), and immunometabolism studies have recently suggested targeting leukocyte bioenergetics in inflammatory diseases. Here, we reveal a peculiar bioenergetic phenotype in circulating Mos of patients with MASH, characterized by high levels of glycolysis and mitochondrial (mt) respiration. The enhancement of mt respiratory chain activity, especially complex II (succinate dehydrogenase [SDH]), is unbalanced toward the production of reactive oxygen species (ROS) and is sustained at the transcriptional level with the involvement of the AMPK-mTOR-PGC-1α axis. The modulation of mt activity with dimethyl malonate (DMM), an SDH inhibitor, restores the metabolic profile and almost abrogates cytokine production. Analysis of a public single-cell RNA sequencing (scRNA-seq) dataset confirms that in murine models of MASH, liver Mo-derived macrophages exhibit an upregulation of mt and glycolytic energy pathways. Accordingly, the DMM injection in MASH mice contrasts Mo infiltration and macrophagic enrichment, suggesting immunometabolism as a potential target in MASH., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Three-component reaction of dimethyl malonate with α,β-acetylenic aldehydes and cyclic secondary amines (pyrrolidine, piperidine, morpholine, and piperazine) under mild conditions afforded dimethyl 2-(3-aminoprop-2-en-1-ylidene)malonates in 50–91% yields. The products were formed preferentially as E isomers, and the described reaction provides a convenient method for the synthesis of push–pull buta-1,3-dienes that are interesting as fluorescent, solvatochromic, and nonlinear optical materials and starting compounds in the synthesis of carbo- and heterocycles. A plausible reaction mechanism involves Knoevenage condensation of dimethyl malonate with α,β-acetylenic aldehyde to give dimethyl 2-(prop-2-yn-1-ylidene)malonate and subsequent nucleophilic addition of cyclic amine to the latter. [ABSTRACT FROM AUTHOR]

In this paper, we describe the reactivity of our previously reported (η3-allyl)dicarbonylnitrosyl iron complexes (1–9). In this context, stoichiometric reactions of 1–9 with dimethyl malonate and di-iso-butyl malonate were carried out. The regioselectivity of the resulting products (10–25) was determined by gas chromatoraphic analysis of reaction mixtures. These products were purified by column chromatography and then structurally characterized by IR, 1H NMR, 13C NMR spectroscopies and mass spectrometry. Effect of different ligands L (L = CO, PPh3, SIMES (1,3-di-tert-butylimidazolium hexafluoro phosphate), BUSI(1,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydro-3H-imidazol-1-ium hexafluorophosphate)) and their influence on the substitution pattern has also been studied. The introduction of variable substituents exhibited diverse reactivities. Generally, it was observed that the reactivity decreased by increasing the size of substituentin (η3-allyl)dicarbonylnitrosyl iron complexes (1–9). Strong impact on the reactivity was observed due to substitution pattern of the allyl moiety. A considerable reduction in the conversion ratio from 81% to 68% was observed in repositioning the substituent from C-3 to C-2 position.

Background: Acute kidney injury (AKI), often experienced at the intensive care units, is associated with high morbidity/mortality where ischemia-reperfusion injury is a main causative factor. Succinate accumulation during ischemia contributes to the excessive generation of reactive oxygen species at reperfusion. Inhibition of succinate dehydrogenase has been associated with protective outcome in cardiac ischemia-reperfusion after 24h, but the effects on kidney and mitochondrial functions are less well studied., Aim: To investigate the therapeutic potential of succinate dehydrogenase inhibition, by using dimethyl malonate (DMM), on kidney and mitochondria functions in a mouse model of AKI., Methods: Male C57BL/6J mice were pre-treated with DMM or placebo, i.p. 30min prior to bilateral renal ischemia (20min). After 3-days of reperfusion, glomerular filtration rate (GFR) was calculated from plasma clearance of FITC-inulin. Kidney mitochondria was isolated and mass specific and intrinsic mitochondrial function were evaluated by high resolution respirometry. Kidney sections were stained (i.e., hematoxylin-eosin and TUNEL) and analyzed for histopathological evaluation of injuries and apotosis, respectively. NADPH oxidase activity in kidney and human proximal tubular cell-line (HK2) were measured luminometrically., Results: DMM treatment improved GFR (p < 0.05) and reduced levels of blood urea nitrogen (p < 0.01) compared to untreated animals, which was associated with lower degree of ischemia-reperfusion-induced tubular injuries (P < 0.001) and apoptosis (P < 0.01). These therapeutic renal effects were linked with improved mitochondrial function, both mass-specific and intrinsic. Finally, DMM treatment prevented ischemia-reperfusion-induced NADPH oxidase activity in the kidney (p < 0.001), which was showed also in HK2 cells exposed to hypoxia and reoxygenation (P < 0.01)., Conclusion: Inhibition of succinate dehydrogenase with DMM, in conjunction with the ischemia-reperfusion phase, significantly improved both renal and mitochondrial functions. These findings may have clinical implications for future therapeutic strategies to prevent development of AKI and associated adverse complications, especially in high risk hospitalized patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. none, (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In addition to its energy-supplying function, increasing evidence suggests that mitochondria also play crucial roles in the regulation of inflammation. Succinate dehydrogenase is also known as mitochondrial complex II, and inhibition of succinate dehydrogenase by dimethyl malonate has been reported to suppress the production of pro-inflammatory cytokines. In the present study, the potential anti-inflammatory benefits of dimethyl malonate were investigated in a mouse model with LPS/ d -galactosamine-induced acute hepatic damage. Male BALB/c mice were injected i.p. with LPS and d -galactosamine to cause liver injury. The degree of liver injury, inflammatory response and oxidative stress and the survival of the experimental animals were determined. The results indicated dimethyl malonate decreased the level of aminotransferases in plasma, alleviated histological abnormalities in liver, inhibited the induction of TNF-α and IL-6 in plasma, suppressed hepatocyte apoptosis and improved the survival of LPS/ d -galactosamine-exposed mice. Therefore, inhibition of succinate dehydrogenase by dimethyl malonate significantly alleviated LPS/ d -galactosamine-induced hepatic damage, which suggests that succinate dehydrogenase might become a novel target for the intervention of inflammation-based hepatic disorders. [ABSTRACT FROM AUTHOR]

1,2,3,4,5-Pentacarbomethoxycyclopentadiene (PCCP) is a strong organic acid and a precursor to useful organocatalysts, including chiral Brønsted acids and silicon-based Lewis acids. The synthetic route to PCCP, first reported in 1942, is inconvenient for a number of reasons. The two-step synthesis requires the purification of intermediates from intractable side-products, high reaction temperatures, and extensive labor (3 days). We have developed an improved procedure that delivers PCCP efficiently in 24 hours in one pot at ambient temperature and without isolation. [ABSTRACT FROM AUTHOR]

Microglia activation drives the pro-inflammatory activity in the early stages of Alzheimer's disease (AD). However, the mechanistic basis is elusive, and the hypothesis of targeting microglia to prevent AD onset is little explored. Here, we demonstrated that upon LPS exposure, microglia shift towards an energetic phenotype characterised by high glycolysis and high mitochondrial respiration with dysfunction. Although the activity of electron transport chain (ETC) complexes is boosted by LPS, this is mostly devoted to the generation of reactive oxygen species. We showed that by inhibiting succinate dehydrogenase (SDH) with dimethyl malonate (DMM), it is possible to modulate the LPS-induced metabolic rewiring, facilitating an anti-inflammatory phenotype. DMM improves mitochondrial function in a direct way and by reducing LPS-induced mitochondrial biogenesis. Moreover, the block of SDH with DMM inhibits the recruitment of hypoxia inducible-factor 1 α (HIF-1α), which mediates the induction of glycolysis and cytokine expression. Similar bioenergetic alterations were observed in the microglia isolated from AD mice (3xTg-AD), which present high levels of circulating LPS and brain toll-like receptor4 (TLR4). Moreover, this well-established model of AD was used to show a potential effect of SDH inhibition in vivo as DMM administration abrogated brain inflammation and modulated the microglia metabolic alterations of 3xTg-AD mice. The RNA-sequencing analysis from a public dataset confirmed the consistent transcription of genes encoding for ETC subunits in the microglia of AD mice (5xFAD). In conclusion, TLR4 activation promotes metabolic changes and the pro-inflammatory activity in microglia, and SDH might represent a promising therapeutic target to prevent AD development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In this paper, we describe the reactivity of our previously reported (η³-allyl)dicarbonylnitrosyl iron complexes (1-9). In this context, stoichiometric reactions of 1-9 with dimethyl malonate and di-iso-butyl malonate were carried out. The regioselectivity of the resulting products (10-25) was determined by gas chromatoraphic analysis of reaction mixtures. These products were purified by column chromatography and then structurally characterized by IR, ¹H NMR, 13C NMR spectroscopies and mass spectrometry. Effect of different ligands L (L = CO, PPh3, SIMES (1,3-di-tert-butylimidazolium hexafluoro phosphate), BUSI(1,3-bis(2,4,6- trimethyl-phenyl)-4,5-dihydro-3H-imidazol-1-ium hexafluorophosphate)) and their influence on the substitution pattern has also been studied. The introduction of variable substituents exhibited diverse reactivities. Generally, it was observed that the reactivity decreased by increasing the size of substituentin (η³-allyl)dicarbonylnitrosyl iron complexes (1-9). Strong impact on the reactivity was observed due to substitution pattern of the allyl moiety. A considerable reduction in the conversion ratio from 81% to 68% was observed in repositioning the substituent from C-3 to C-2 position. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the alterations of myocardial succinate and fumarate levels with or without succinate dehydrogenase (SDH) inhibitor dimethyl malonate during 24 h of lipopolysaccharides (LPS) challenge, as well as the effects of dimethyl malonate on the impaired cardiac tissue. Myocardial succinate and fumarate levels were increased in the initial 9 h of LPS challenge. During this time, dimethyl malonate increased the succinate level, decreased the fumarate level, aggravated the cardiac dysfunction, reduced the oxidative stress, had little effect on interleukin-1β production, promoted interleukin-10 production and bothered the ATP production. Co-treatment with exogenous succinate significantly increased interleukin-1β production in this period. After 12 h of LPS challenge, myocardial the succinate level increased sharply, while the fumarate level gradually decreased. During 12–24 h of LPS challenge, dimethyl malonate effectively reduced the succinate level, increased the fumarate level, improved cardiac dysfunction, inhibited interleukin-1β production, and had little effect on oxidative stress, interleukin-10 production, and ATP production. LPS challenge also significantly increased the myocardial succinate receptor 1 expression and circulating succinate level. Inhibition of succinate receptor 1 significantly reduced the mRNA expression of interleukin-1β. In conclusion, the current study suggests that myocardial succinate accumulates during LPS challenge, and that SDH activity may be transformed (from forward to reversed) and involved in a line of stress response. Dimethyl malonate inhibits SDH and, depending on the time of treatment, reduces LPS-induced cardiac impairment. Furthermore, accumulated succinate exerts pro-inflammatory effects partly via succinate receptor 1 signaling. [Display omitted] • Myocardial succinate level experiences a sharp degree of increase after 12 h of lipopolysaccharides (LPS) challenge. • Myocardial succinate dehydrogenase (SDH) activity is forward in the initial 9 h of LPS challenge, while it is reversed after 12 h. • SDH inhibition by dimethyl malonate protects the LPS-induced cardiac impairment. • Succinate receptor 1 (SUCNR1) expression is elevated in LPS-stimulated myocardium, and accumulated succinate promotes the IL-1β production possibly through activating SUCNR1. [ABSTRACT FROM AUTHOR]

The treatment of dimethyl malonate with LHMDS in anhydrous THF (condensed-phase) generates, in addition to the expected corresponding lithium enolate, methyl formate anion (or methoxycarbonyl anion, − COOMe) which can react with several electrophiles to give corresponding methoxycarbonyl derivatives by nucleophilic substitution reaction. [ABSTRACT FROM AUTHOR]

A practical and chemoselective method is described for the O-methylation of carboxylic acids. Dimethyl malonate, a low toxic and commercially available compound was found to be an effective methylating reagent for a variety of carboxylic acids affording methyl ester products in good to high yields and with excellent chemoselectivity, without the use of strong bases as additives. A mechanism involving the utilization of potassium bromide is tentatively proposed. [ABSTRACT FROM AUTHOR]

A NaI-mediated α -functionalization of dimethyl malonate and its derivatives with carboxylic acids has been developed. Two different reaction routes based on the same substrates and reaction conditions by simply altering the reaction temperature have been observed, which led to the synthesis of two types of products in good to high yields. The scope of substrates was investigated for both types of reactions, respectively, and possible reaction mechanisms were suggested. [ABSTRACT FROM AUTHOR]