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Chemical Structure| 516-05-2 Chemical Structure| 516-05-2
Chemical Structure| 516-05-2

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Methylmalonate (MMA) is a dicarboxylic acid that can be derived from methylmalonyl-coenzyme A (methylmalonyl-CoA).

Synonyms: Methylpropanedioic acid; Methylmalonate; NSC 25201

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Wiltsie, Vanessa E ;

Abstract: Antimicrobial resistance (AMR) is a pressing issue facing modern medicine today. Bacteria are developing resistance to antibiotics faster than new antibiotics can be brought to market. Antimicrobial resistant infections are responsible for increased morbidity and mortality rates, as well as an economic burden with increased duration of care and costs of treatments. The development of new antibiotics to combat bacterial resistance is a long and costly process and has resulted in pharmaceutical companies turning away from the traditional drug development pipeline. One alternative method to address AMR is through repurposing existing approved drugs such as by utilizing combination drug therapies. Combination drug therapies often involve the inhibition of antibiotic modifying enzymes found within bacteria. This research aims to use combination therapy to restore the functionality of the drug fosfomycin by using in silico high-throughput virtual screening (HTVS) to identify inhibitors of fosfomycin resistance enzymes. The purpose of this work is to characterize fosfomycin resistance enzymes and identify enzymatic inhibitors to restore the functionality of fosfomycin. First, we identified and characterized the fosfomycin resistance enzyme in Enterococcus faecium (FosBEf). Our goal was to structurally characterize the bacillithiol binding site, however we discovered FosBEf is unique among the FosB enzyme family and utilizes L-cys as the preferred thiol substrate and produced limited enzymatic activity with BSH. Next, we focused on identifying and characterizing inhibitors of the fosfomycin resistance protein in Pseudomonas aeruginosa (FosAPa). Initially we compared the structural and kinetic properties of established inhibitors of other classes of fosfoymcin resistance enzymes on FosA. Then we utilized in silico high-throughput virtual screening (HTVS) to identify halogenated inhibitors to modify the absorption, distribution, metabolism, and excretion properties and potential permeability into P. aeruginosa. Taken together, the findings of this work provide a scaffold for future structure-based drug design for restoring fosfomycin activity.

Keywords: Antimicrobial resistance ; crystallography ; fosfomycin ; glutathione

Purchased from AmBeed: ;

Travis, Skye ; Green, Keith D. ; Thamban Chandrika, Nishad ; Pang, Allan H. ; Frantom, Patrick A. ; Tsodikov, Oleg V. , et al.

Abstract: Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn2+-dependent L-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus, one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the min. inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus. Our results will inform future studies on inhibitor design for the FosB enzymes.

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Alternative Products

Product Details of Methylmalonic acid

CAS No. :516-05-2
Formula : C4H6O4
M.W : 118.09
SMILES Code : CC(C(O)=O)C(O)=O
Synonyms :
Methylpropanedioic acid; Methylmalonate; NSC 25201
MDL No. :MFCD00002656
InChI Key :ZIYVHBGGAOATLY-UHFFFAOYSA-N
Pubchem ID :487

Safety of Methylmalonic acid

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of Methylmalonic acid

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 516-05-2 ]

[ 516-05-2 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 871700-22-0 ]
  • [ 516-05-2 ]
  • [ 871700-24-2 ]
YieldReaction ConditionsOperation in experiment
With acetic anhydride; at 100℃; for 3.0h;Product distribution / selectivity; Under a nitrogen atmosphere, to 3-cyclopropyl-l-(2-fluoro- 4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 (34.4 g) and 2-methyl-malonic acid 54 (15.2 g) was added acetic anhydride (34.4 ml), and the mixture was stirred with heating at 100C for 3 hrs. After allowing to cool to 50C, acetone (68.8 ml) was added dropwise, and the mixture was stirred as it was for 30 min. Water (172 ml) was further added dropwise, and the mixture was stirred for 1 hr. After allowing to cool to room temperature with stirring, the precipitated crystals were collected by filtration and dried to give crude crystals (37.7 g, LC purity 91%) of 3- cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl- lH,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55. Isopropanol (92.0 ml) was added to the obtained crude crystals (30.7 g), and the mixture was stirred at room temperature for 4 hrs. The crystals were collected by filtration and dried to give 3-cyclopropyl-l-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3- d]pyrimidine-2,4,7-trione 55 (25.9 g, yield from 76,58%) as pale-yellow crystals.
  • 2
  • [ 871700-23-1 ]
  • [ 871700-22-0 ]
  • [ 516-05-2 ]
  • C18H15FIN3O4 [ No CAS ]
  • [ 871700-24-2 ]
YieldReaction ConditionsOperation in experiment
21% With acetic anhydride; at 100℃; for 2.0h;Product distribution / selectivity; To a 2: 1 mixture (34.6 g) of 3-cyclopropyl-l-(2-fluoro-4- iodophenyl)-6-methylamino-lH-pyrimidine-2,4-dione 52 and 1- cyclopropyl-3-(2-fluoro-4-iodo-phenyl)6-methylamino-1H- pyrimidine-2,4, -dione 53 obtained in Step 4, and 2-methylmalonic acid 54 (10.2 g) was added acetic anhydride (173 ml), and the mixture was stirred at 100C for 2 hrs. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. Acetone (104 ml) was added to the residue, and the mixture was stirred with heating under reflux for 30 min. After allowing to cool to room temperature, the precipitated crystals were collected by filtration and dried to give 3- cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl- lH,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (15.1 g, yield from 48,21%) as colorless crystals.
  • 3
  • [ 516-05-2 ]
  • [ 78775-11-8 ]
  • 3-(4-bromo-3-methylphenyl)-2-methylacrylic acid [ No CAS ]
  • 4
  • [ 516-05-2 ]
  • [ 71510-95-7 ]
  • ethyl 1,5-dimethyl-2,4,6-pyridin-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; toluene; at 20 - 35℃; for 56h; S1: oxalyl chloride (13.4 mL, 153 mmol) was slowly added dropwise to a suspension of methylmalonic acid (9.0 g, 76.2 mmol) and DMF (2 drops) in dichloromethane (450 mL).After reacting at room temperature for 20 h, the solution was homogeneous and slowly added dropwise to a solution of malonic acid <strong>[71510-95-7]monoformamide monoethyl ester</strong> (8.13 g, 56 mmol) in dry toluene (82 mL).Continue to react at 35 C for 36 h, add NaOH solution (0.8 mol / L, 82 mL),Dispense, take the solution layer, continue to add NaOH solution in the organic layer(0.8 mol/L, 82 mL), the combined layers were washed with dichloromethane (164 mL).Concentrated hydrochloric acid to adjust the pH to 1, and ethyl acetate (50 mL once for 3 times) to extract the aqueous layer.The ethyl acetate phases were combined, dried, filtered and concentrated to give a crude material.Directly invest in the next step;
 

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