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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
2-naphthol has a role as an antinematodal drug, a genotoxin and a human xenobiotic metabolite. It is also a metabolite of naphthalene.
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Surveying the scope of aromatic decarboxylations catalyzed by prenylated-flavin dependent enzymes
Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto ; Prathamesh M. Datar ; Daniel J. DiRocco ; Katherine Huntera and E. Neil G. Marsh
Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.
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Purchased from AmBeed: 27916-43-4 ; 2438-05-3 ; 501-89-3 ; 42287-94-5 ; 776-79-4 ; 53473-36-2 ; 7251-61-8 ; 42287-97-8 ; 1621-91-6 ; 37718-11-9 ; 288-13-1 ; 86-73-7 ; 104-53-0 ; 2018-90-8 ; 87-66-1 ; 135-19-3 ; 1664-57-9 ; 289-80-5 ; 693-95-8 ; 55-22-1 ; 102-93-2 ; 1477-50-5 ; 1632-76-4 ; 4780-79-4 ; 16642-79-8 ; 3581-89-3 ; 501-97-3 ; 771-50-6 ; 98-98-6 ; 619-64-7 ; 100-51-6 ; 402-45-9 ; 59-67-6 ; 93-60-7 ; 273-53-0 ; 2084-13-1 ; 51-17-2 ; 2459-09-8 ; 2459-07-6 ; 95-16-9 ; 459-31-4 ; 90-05-1 ; 150-76-5 ; 103-25-3 ; 271-44-3 ; 6293-56-7 ; 2550-26-7 ; 288-32-4 ; 501-52-0 ; 2001-32-3 ; 1592-38-7 ; 95-15-8 ; 91-19-0 ; 1122-61-8 ; 3724-19-4 ; 20173-24-4 ; 118-31-0 ; 6125-24-2 ; 60-12-8 ; 90-15-3 ; 120-72-9 ; 822-36-6 ; 288-47-1 ; 288-42-6 ; 2038-57-5 ; 38628-51-2 ; 1929-29-9 ; 15009-91-3 ; 1505-50-6 ; 581-40-8 ; 616-47-7 ; 1571-33-1
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Berg, Kaja ; Hegde, Pooja ; Pujari, Venugopal ; Brinkmann, Marzena ; Wilkins, David Z. ; Parish, Tanya , et al.
Abstract: The electron transport chain (ETC) in the cell membrane consists of a series of redox complexes that transfer electrons from electron donors to acceptors and couples this electron transfer with the transfer of protons (H+) across a membrane. This process generates proton motive force which is used to produce ATP and a myriad of other functions and is essential for the long-term survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), under the hypoxic conditions present within infected granulomas. Menaquinone (MK), an important carrier molecule within the mycobacterial ETC, is synthesized de novo by a cluster of enzymes known as the classic/canonical MK biosynthetic pathway. MenA (1,4-dihydroxy-2-naphthoate prenyltransferase), the antepenultimate enzyme in this pathway, is a verified target for TB therapy. In this study, we explored structure-activity relationships of a previously discovered MenA inhibitor scaffold, seeking to improve potency and drug disposition properties. Focusing our campaign upon three molecular regions, we identified two novel inhibitors with potent activity against MenA and Mtb (IC50 = 13-22 μM, GIC50 = 8-10 μM). These analogs also displayed substantially improved pharmacokinetic parameters and potent synergy with other ETC-targeting agents, achieving nearly complete sterilization of Mtb in combination therapy within two weeks in vivo. These new inhibitors of MK biosynthesis present a promising new strategy to curb the continued spread of TB.
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Keywords: 1,4-dihydroxy-2-naphthoate prenyltransferase ; MenA ; MenA inhibitors ; Menaquinone ; Mtb ; Mycobacterium tuberculosis ; Piperidine derivatives ; SAR
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Purchased from AmBeed: 25952-53-8 ; 90719-32-7 ; 872-85-5 ; 6457-49-4 ; 3769-41-3 ; 10338-57-5 ; 135-19-3 ; 135-19-3 ; 28177-48-2 ; 22246-18-0 ; 122334-37-6 ; 91914-06-6 ; 10040-98-9 ; 161975-39-9 ; 150-76-5 ; 371-41-5 ; 63754-96-1 ; 288-32-4 ; 3380-34-5 ; 1677-46-9 ; 166815-96-9 ; 700-57-2 ; 1204-86-0 ; 21725-69-9 ; 367-12-4 ; 1003-29-8 ; 627-35-0 ; 27292-49-5 ; 104324-16-5 ; 123855-51-6 ; 180847-23-8 ; 4328-13-6 ; 875401-70-0 ; 405272-71-1 ; 63614-86-8 ; 1420942-13-7 ; 25952-53-8 ; 1420895-21-1 ; 1078-18-8 ; 32363-45-4 ; 69564-68-7 ; 31519-22-9 ; 22246-18-0 ; 189618-33-5 ; 180847-24-9 ; 6264-98-8 ; 946680-75-7 ; 63608-38-8 ; 713-68-8 ; 62810-39-3 ; 189618-32-4 ; 63608-31-1 ; 15789-05-6 ; 63712-27-6 ; 63608-33-3 ; 63608-35-5
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CAS No. : | 135-19-3 |
Formula : | C10H8O |
M.W : | 144.17 |
SMILES Code : | OC1=CC=C2C=CC=CC2=C1 |
MDL No. : | MFCD00004067 |
InChI Key : | JWAZRIHNYRIHIV-UHFFFAOYSA-N |
Pubchem ID : | 8663 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302+H332-H317-H318-H400 |
Precautionary Statements: | P261-P264-P270-P271-P272-P273-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338+P310-P333+P313-P391-P501 |
Class: | 9 |
UN#: | 3077 |
Packing Group: | Ⅲ |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A solution of amide 1a (310 mg, 1.5 mmol, 1 equiv) and 2-ClPyr (169 muL, 1.8 mmol, 1.2 equiv) in CH2Cl2 (10 mL) was cooled to -78 C with dry ice in acetone, and Tf2O (277 muL, 1.65 mmol, 1.1 equiv) was added via syringe under an argon atmosphere. After 5 min, the reaction mixture was warmed to 0 C and 2-naphthol (216 mg, 1.5 mmol, 1 equiv) was added. The mixture was allowed to warm to 25 C and stirred for another 3 h. The progress of the reaction was monitored by TLC. After completion, aq. NaOH (10 mL, 0.1 M) was added in order to neutralize the acidic salts. The organic phase was separated, washed with brine (10 mL), and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the residue purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford 2a as a white solid (480 mg, 96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.4% | With sodium hydrogensulfite; In water; at 120℃; | 2-naphthol (20.0 g, 138.8 mmol), NaHSO3 (28.8 g, 277.4 mmol), distilled water (160 mL) and 4-bromophenylhydrazine (31.2 mL, 166.4 mmol) were heated to TheAfter 12 hours distilled water was added and the resulting solid was filtered off under reduced pressure.The solid thus obtained was added to aqueous HCl and heated to 100°After 1 hour, following extraction with dichloromethane, the product was washed with distilled water and aqueous NaOH solution. Column separation gave compound A (9.2 g, 31.0 mmol, 22.4%). |
With sodium hydrogensulfite; In water; at 120℃; for 12h; | 20.0 g (138.8 mmol) of 2-naphthol, 28.8 g (277.4 mmol) of NaHSO3, 160 mL of distilled water, and 31.2 mL (166.4 mmol) of 4-bromophenylhydrazine were heated to 120. After 12 hours, the reaction mixture was added with distilled water, and the produced solid was vacuum filtered. The solid thus obtained was added to an aqueous hydrochloric acid solution and heated to 100. After 1 hour, the resultant product was extracted with dichloromethane, washed with distilled water and aqueous NaOH, and purified by column separation, thus obtaining 9.2 g (31.0 mmol) of Compound 2-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With glucose sulfonic acid; In water; at 90℃; for 3h; | General procedure: A mixture of aromatic aldehydes (1, 2.0 mmol), dimedone (2, 2.0 mmol), 2-naphthol or beta-naphthylamine (3 or 4, 2.0 mmol) and 5 molpercent GSA was stirred in water (2 mL) at 90 °C until completely (monitored by TLC). After the completion, water (20?25 mL) was added to quench the reaction and then the reaction mixture was filtered, concentrated, the precipitate was collected, and purified by 95percent EtOH/DMF (8:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium 2-oxoimidazolidine-1,3-diide; In water; at 20℃; for 2h;Green chemistry; | General procedure: A mixture containing aldehyde (1 mmol), beta-naphthol (1 mmol; 1.44 g), 4-hydroxycoumarin (1 mmol; 1.62 g), 1mmol% of POImD and 10mL H2O were stirred at room temperature for the required reaction times. The progress of the reaction was monitored by TLC (EtOAc: petroleum ether 1:4). Having completed the reaction, we extracted the product with CHCl3/H2O. After separation of phases and evaporation of the organic phase and recrystallizationof the residue, the pure product was obtained. The aqueous phase was concentrated under reduced pressure to recover the catalyst for subsequent use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium fluoride; In acetonitrile; at 20 - 25℃; for 2h; | Thetetrafluoro Phthalo nitrile (compound (5)) 6.0 g (30mmol), and the potassiumfluoride 15 g (1.2eq.) and acetonitrile 20ml were put in the reactor in whichthe entrance of 100ml placing the thermometer was 4 and it was stirred and it cooledto 0. Here, beta - naphthol (compound(a-2)) 4.3 g (1.0eq.) was little by little injected. In 5 or less the mixture after theinput end, after it reacted at 1 hour the temperature was risen to 20 and it reacted 2 hours at 20 through 25. The solid emitting thereaction mixture to water and was segregated was filtered and it took out afterthe completion of reaction. The obtained preparation was well wiped off withthe methanol and the compound (4-2) 6.7g of the white solid was obtained(the yield 69percent). |
69% | With potassium fluoride; In acetonitrile; at 5 - 20℃; for 3h; | A thermometer attached to a 100ml four-necked reactor, <strong>[1835-65-0]tetrafluorophthalonitrile</strong> (compound (5)) 6.0g (30mmol), potassium fluoride 21g (36mmol, 1.2 eq.) and acetonitrile into a 50ml, stirring under a 5 it cooled. Here, beta- naphthol (compound (a-1)) was added dropwise to 4.3g (30mmol, 1.0eq.). After the addition was completed, the mixture was reacted for 1 hour at less than 5, heated to room temperature and allowed to react for 2 hours. After the reaction, the reaction mixture was taken out by releasing the water, and filtering the precipitated solid. Resulting crude by well washing the product with isopropanol and dried to obtain the compound (4-1), 6.7g, as a white solid (yield 69percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: To a mixture of compound 3(1.5 mmol) and 3M HCl (1.53 mL) at 0 °C, a solution of sodium nitrite (NaNO2, 1.58mmol) in water (3 mL) was added dropwise while maintaining the temperaturebelow 5 °C. After stirring for 30 min, asolution of diazonium chloride was prepared. Subsequently, a solution ofdiazonium chloride was added gradually to a mixture of phenols/anilines (4a,b; 6a?f;8a?k or 9a?e, 1.5 mmol), and ethanol (3 mL) at 0-5 °C. The reaction mixture was adjusted to pH 8-9 with 1 Maq. NaOH. After addition, the mixture was continued to stir for 3-6 h. Thesolid was collected, washed with water (3×15 mL), dried and purified by PTLC orsilica gel column chromatography to give the target products IIa?x. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
106.9 mg | With sodium carbonate; In acetonitrile; at 120℃; for 24h;Schlenk technique; | General procedure: A mixture of phenol 1 (0.50 mmol), Na2CO3 (10.6 mg, 0.10mmol, 20 mol%), and alkenyl carboxylate (2.0 mmol, 4.0 equiv)in MeCN (3 mL) was added to a Schlenk flask (25 mL) and stirredat r.t. The mixture was stirred at 120 C until the reaction wasfinished. Then, the solvent was evaporated under reduced pressureand the residue was purified by column chromatography(petroleum ether/ethyl acetate 20:1 to 10:1) to afford theproduct 3. |