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Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents
Walczak, Juliusz Maksymilian ; Iwaszkiewicz-Grzes, Dorota ; Ziomkowska, Michalina , et al. J. Enzym. Inhib. Med. Ch.,2022,37(1):2725-2741. DOI: 10.1080/14756366.2022.2127701 PubMed ID: 36189734
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Abstract: The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.
Keywords: Mycophenolic acid ; amide derivatives ; heterocycles ; benzoxazole ; IMPDH inhibition
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CAS No. : | 1123-93-9 | MDL No. : | MFCD04115282 |
Formula : | C7H6N2S | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | UJZYHMZRXGNDFB-UHFFFAOYSA-N |
M.W : | 150.20 | Pubchem ID : | 70749 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* 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 |
---|---|---|
52% | A mixture OF 5-NITRO-1, 3-benzothiazole (Description 5,1. 9 g, 11 mmol) and tin (II) chloride dihydrate (8.6 g, 38 mmol) in 2-propanol (30 ml) was heated to reflux for 24 h. The cooled reaction mixture was poured onto an ice/water mixture (85 ml) and adjusted to pH7 with sodium hydroxide (s). The mixture was extracted with ethyl acetate (3 X 50 ml) and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica (eluant 1 : 1 hexane: ethyl acetate) to give 1, 3-benzothiazol-5-amine (820 mg, 52 %). LHNMR (CDCL3) 6 6.85 (1H, dd, J2. 3,8. 6), 7.40 (1H, d, J2. 1), 7.66 (1H, d, J 8.4), 8.90 (1H, s). | |
With stannous chloride; | 5-Aminobenzothiazole To a solution of SnCl2 (7.0 g, 8.8 mmol) and 14 mL of con.HCl was added 5-nitrobenzothiazole (0.65 g, 3.6 mmol) in a portion and resulting reaction mixture was stirred for 1 h at 25 C. The reaction mixture was basified with aqueous NaOH and extracted with EtOAc. Combined organic layers were dried over Na2 SO4 and concentrated in vacuo, yielding an oil (0.47 g, 3.2 mmol, 89%) which was identified as the amine (>95% pure) and subjected to the following reaction without further purification. | |
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; | Step 9.2: 5-Amino-benzothiazole Purified 5-nitro-benzothiazole (7.2 g, 0.04 mol, see WO 98/23612, example 7A), dissolved in 160 mL of methanol and 160 mL of THF, is hydrogenated in the presence of 1.6 g Pd/C (10%; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated and the residual oil purified by flash chromatography on silica gel using dichloromethanol/methanol 97:3 as eluent. The title compound is obtained as a colorless solid: m.p. 76-78 C., HPLC tR=0.76 min; MS-ES+: (M+H)+=151; Rf (dichloromethane/methanol 97:3)=0.76. |
With hydrogen;10% palladium on activated carbon; In tetrahydrofuran; methanol; | Purified 5-nitro-benzothiazole (7.2 g, 0.04 mol, see WO 98/23612, example 7A), dissolved in 160 mL of methanol and 160 mL of THF, is hydrogenated in the presence of 1.6 g Pd/C (10 %; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated and the residual oil purified by flash chromatography on silica gel using dichloromethanol/methanol 97:3 as eluent. The title compound is obtained as a colorless solid: m.p. 76-78 0C, HPLC tR = 0.76 min; MS-ES+: (M+H)+ = 151 ; Rf (dichloromethane/methanol 97:3) = 0.76. | |
5-Nitrobenzo[d]thiazole (150 mg) was dissolved in THF (20 mL) at 0 0C and AcOH (1 mL) was added followed by Zinc dust (1.65 g). Mixture was stirred at RT for 1 h and was filtered on silica pad (rinsed with EtOAc). Solvent was evaporated, residue was diluted with NaHCO3 and extracted with EtOAc. Organic phases was dried, filtered and evaporated to give benzo[d]thiazol-5-amine. | ||
2.1 g | With tin(II) chloride dihdyrate; In ethyl acetate;Reflux; | A mixture of 5-nitrobenzo[d]thiazole (3.0 g, 16.7 mmol) and SnCl2*2H2O (19 g, 84.2 mmol) in EtOAc (150 mL) was stirred at reflux overnight. The reaction mixture was basified with Et3N until pH 8 and the precipitate was filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EtOAc/DCM = 2:1) to afford the title compound as a yellow solids (2.1 g). 1H NMR (400 MHz, CDCl3): oe 8.92 (s, 1H), 7.69 (d, 1H), 7.41 (d, 1H), 6.86 (dd, 1H), 3.82 (brs, 2H); LCMS: 151 (M+H). |
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