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Yuan, Gengyang ; Dhaynaut, Maeva ; Lan, Yu ; Guehl, Nicolas J. ; Huynh, Dalena ; Iyengar, Suhasini M. , et al.
Abstract: Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.
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Purchased from AmBeed: 16289-54-6 ; 5521-55-1 ; 22047-25-2 ; 98-80-6 ; 40155-47-3 ; 5720-05-8 ; 879-65-2 ; 98-96-4 ; 31519-62-7 ; 23688-89-3 ; 23611-75-8 ; 33332-25-1 ; 20737-42-2 ; 61442-38-4 ; 17933-03-8 ; 50681-25-9 ; 13924-99-7 ; 40155-43-9 ; 166744-78-1 ; 36070-80-1 ; 4595-61-3 ; 118853-60-4 ; 41110-28-5 ; 40155-42-8 ; 937669-80-2 ; 31462-59-6 ; 16419-60-6 ; 5424-01-1 ; 59-67-6 ; 34604-60-9 ; 27398-39-6 ; 1196151-53-7 ; 19847-12-2 ; 13965-03-2 ; 876161-05-6 ; 27825-21-4 ; 2164-61-6 ; 4604-72-2 ; 98-97-5 ; 24005-61-6 ; 5521-61-9 ; 2516-34-9 ; 2719-27-9 ; 123-90-0 ; 6761-50-8 ; 625-43-4 ; 872-64-0 ; 1309866-36-1 ; 36932-49-7 ; 1528085-68-8 ; 1195533-51-7 ; 13534-79-7
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Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents
Hegde, Pooja V. ; Aragaw, Wassihun W. ; Cole, Malcolm S. ; Jachak, Gorakhnath ; Ragunathan, Priya ; Sharma, Sachin , et al.
Abstract: Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the CoA biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative mols. were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic anal. of these analogs may lead to a next generation POA analog for treating TB.
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Keywords: Tuberculosis ; Pyrazinoic acid ; pyrazinamide
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Purchased from AmBeed: 16289-54-6 ; 5521-55-1 ; 22047-25-2 ; 98-80-6 ; 40155-47-3 ; 5720-05-8 ; 879-65-2 ; 98-96-4 ; 31519-62-7 ; 23688-89-3 ; 23611-75-8 ; 33332-25-1 ; 20737-42-2 ; 61442-38-4 ; 17933-03-8 ; 50681-25-9 ; 13924-99-7 ; 40155-43-9 ; 36070-80-1 ; 4595-61-3 ; 118853-60-4 ; 41110-28-5 ; 40155-42-8 ; 937669-80-2 ; 98-98-6 ; 31462-59-6 ; 16419-60-6 ; 5424-01-1 ; 59-67-6 ; 34604-60-9 ; 27398-39-6 ; 1196151-53-7 ; 19847-12-2 ; 13965-03-2 ; 876161-05-6 ; 27825-21-4 ; 2164-61-6 ; 4604-72-2 ; 98-97-5 ; 24005-61-6 ; 103-67-3 ; 5521-61-9 ; 2516-34-9 ; 2719-27-9 ; 123-90-0 ; 6761-50-8 ; 625-43-4 ; 872-64-0 ; 36932-49-7 ; 1528085-68-8 ; 1195533-51-7 ; 13534-79-7
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CAS No. : | 2719-27-9 |
Formula : | C7H11ClO |
M.W : | 146.61 |
SMILES Code : | O=C(Cl)C1CCCCC1 |
MDL No. : | MFCD00001456 |
InChI Key : | RVOJTCZRIKWHDX-UHFFFAOYSA-N |
Pubchem ID : | 75938 |
GHS Pictogram: | ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H227-H314-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3265 |
Packing Group: | Ⅱ |
* 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 |
---|---|---|
With pyridine; In diethyl ether; for 10h; | To an ether solution (5 mL) of cyclohexanecarboxylic acid (250 mg, 1.95 mmol) was added pyridine (0.5 mL) and cyclohexanecarbonyl chloride (286 mg, 0.261 mL, 1.95 MMOL). After 10 h, the suspension was diluted with ether (20 mL), washed with ice-cold 5% HCl solution (1x50 mL) and concentrated NaHCO3 solution (1x50 mL) and dried over Na2S04. All solvent was removed in vacua to give 350 mg of cyclohexanecarboxylic anhydride as A colorless oil. A portion of the cyclohexanecarboxylic anhydride. (226 mg, 0. 948 mmol) was added to a sodium carbonate solution (1 M, 2 mL) of the aminophosphate 21a (110 mg, 0.412 mmol). After 15 h, it was acidified to PH#1 by addition of concentrated HCI solution at 0 C. Preparative HPLC purification afforded 50 mg (36% yield) of the title compound 25-17. 1H NMR (CD3OD) : δ 7. 27-7. 1 (5H, m), 6.67 (1H, br d), 4.34 (1H, br s), 4.08 (1H, m), 3.96 (1H, m), 2.90 (1H, dd, J=14.4, 6.6 Hz), 2. 78 (1H, dd, J=14.9, 9 Hz), 2.10 (1H, br t), 1.79-1. 51 (5H, m), 1. 33-1. 02 (5H, m); LCMS (ESP): 342 (M+H+) ; 340 (M-H)-. | |
With pyridine; In diethyl ether; for 10h; | Example 25-17 Phosphoric acid mono-{2-[(1-cyclohexyl-methanoyl)-amino]-3-phenyl-propyl}ester To an ether solution (5 mL) of cyclohexanecarboxylic acid (250 mg, 1.95 mmol) was added pyridine (0.5 mL) and cyclohexanecarbonyl chloride (286 mg, 0.261 mL, 1.95 mmol). After 10 h, the suspension was diluted with ether (20 mL), washed with ice-cold 5% HCl solution (1*50 mL) and concentrated NaHCO3 solution (1*50 mL) and dried over Na2SO4. All solvent was removed in vacuo to give 350 mg of cyclohexanecarboxylic anhydride as a colorless oil. | |
General procedure: To a flamed-dried flask with magnetic stir bar, was added aliphatic acid (1.0 equiv), dried DCM (1.0 M) and triethylamine (1.05 equiv) successively. The solution was stirred for 30 minutes at 0 0C. Then acyl chloride (1.05 equiv) was added dropwise to the mixture and stirred overnight at rt. The solvent was evaporated by vacuum to afford the crude mixture. And the mixture was dissolved in n-hexane. Then the residue was filtered through a small plug of celite and concentrated to afford the anhydrides. This product was used to next catalytic reaction without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; at 20 - 100℃; for 3h; | A mixture of <strong>[16687-60-8]5-(4-nitro-phenyl)-1H-tetrazol</strong>e (0. 5 g, 2. 62 mmol) and cyclohexane carbonyl chloride (0. 35 mi, 2. 62 mmol) in 3 mi anhydrous pyridine was stirred at room temperature under nitrogen for 20 min, then heated to 60 C for 1 hr and finally heated to 100 C for 2 h. The reaction mixture was cooled to room temperature then poured onto ice (30 g) and the aqueous mixture was extracted with 30 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 30 mi water, 30 mi 1 N aqueous hydrochloric acid solution and 30 mi brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The crude produce was purified by flash column chromatography (silica gel, 40 g), eluting with 4 : 1 hexane/ethyl acetate to yield the title compound as a yellowish solid (0. 5 g, 100% yield). MS : 274. 2 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: TCCA (0.256 g, 1.1 mmol) was portionwise added over a period of 1-2 min to a solution of an aldehyde (1.1 mmol) in 3.25 mL dichloromethane, under dry argon atmosphere and at room temperature. The resulting suspension was stirred at room temperature and under dry argon. The reaction was monitored by TLC until disappearance of the aldehyde. Then the reaction mixture was cooled to 0 C and were added water (1.0 mmol) and NEt3 (0.202 g, 2.0 mmol). After completion of the additions, the reaction mixture left to stir at room temperature until disappearance of the acyl chloride, monitored by TLC. For the products 4a-4g, the solvent was evaporated under reduced pressure and the residue purified by flash chromatography. For the products 4h-4l the reaction mixture was washed three times with a solution of 5 % HCl and then three times with a solution of 5 % NaHCO3; the organic phase was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure providing the desired anhydride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: To a stirred solution of compound 16 (500 mg, 2.7 mmol) in DCM (50 mL), cyclohexanecarbonyl chloride (532 L, 4.0 mmol) was added at 0 C. The mixture was stirred at room temperature overnight. The reaction was quenched with NaHCO3 (aq.), extracted with DCM (50 mL × 3). The organic phases were then processed in the usual way and chromatographed (1:1 petroleum ether/ EtOAc) to afforded compound 19 (350 mg, 43%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 1h; | (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclohexanecarboxamido)butanoic acid Cyclohexanecarbonyl chloride (86 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of <strong>[161420-87-7](S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid</strong> (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0 C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL*1). The crude materials were purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (201 mg, 70%). Analysis LCMS Condition A: Retention time=1.01 min; ESI-MS(+) m/z 451.2 (M+H) 1H NMR (400 MHz, methanol-d4): delta 7.79 (d, J=7.5 Hz, 2H), 7.73-7.65 (m, 2H), 7.43-7.35 (m, 2H), 7.34-7.26 (m, 2H), 4.42-4.30 (m, 2H), 4.27-4.15 (m, 2H), 3.18 (d, J=7.3 Hz, 1H), 2.15 (s, 1H), 2.10-2.01 (m, 1H), 1.89-1.72 (m, 5H), 1.68 (d, J=10.3 Hz, 1H), 1.49-1.17 (m, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 18h; | At a temperature of 0C, a round bottom flask was charged with cyclohexanecarbonyl chloride (465 mg, 3.17 mmol), DCM (15 mL), A1C13 (423 mg, 3.17mmol) and magnetic stir bar. The reaction mixture was allowed to stir and come to rt. Indole 9 (200 mg, 1.06 mmol) was added as a DCM (6 mL) solution over the course of 25 mm. The reaction mixture was then stirred for 18 h. The reaction was quenched with saturated NH4C1, extracted with DCM, dried with Na2SO4, solvent removed under reduced pressure and purified using flash column chromatography. The ester intermediate was hydrolyzed in 2 M NaOH in refluxing MeOH for 4 h. The reaction mixture was cooled, acidified with 1 M HC1 and allowed to solidify upon standing. The carboxylic acid product was collected by vacuum filtration and used without further purification. ?H NIVIR (400 IVIHz, DMSO-d6) 12.60 (br. s., 1H), 8.90 (s, 1H), 8.48 (s, 1H), 7.87 (dd, J= 1.4, 8.8 Hz, 1H), 7.58 (d, J= 9.0 Hz, 1H), 3.88 (s, 3H), 3.11 (t, J 10.3 Hz, 1H), 1.78 (t, J= 11.5 Hz, 4H), 1.68 (d, J= 12.1 Hz, 1H),1.52- 1.30 (m, 4H), 1.26 - 1.14 (m, 1H). ?3C NIVIR (101 IVIHz, DMSO-d6) 198.4, 168.1,139.7, 138.7, 125.7, 124.4, 124.1, 123.9, 114.7, 110.4, 46.4, 33.3, 29.6, 25.6, 25.4. |
Tags: 2719-27-9 synthesis path| 2719-27-9 SDS| 2719-27-9 COA| 2719-27-9 purity| 2719-27-9 application| 2719-27-9 NMR| 2719-27-9 COA| 2719-27-9 structure
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H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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