Abstract: Background/Objectives: Glioblastoma multiforme (GBM), an aggressive and deadly brain tumour, presents significant challenges in achieving effective treatment due to its resistance to current therapies and poor prognosis. This study aimed to synthesise and evaluate 23 novel analogues of 3,4-dihydroquinolin-2(1H)-one, designed to enhance druggability and solubility, and to investigate their potential as VEGFR2 inhibitors for GBM treatment. Methods: The synthesised compounds were analysed using in silico methods, including molecular docking and dynamics studies, to assess their interactions with key residues within the VEGFR2 binding pocket. In vitro evaluations were performed on U87-MG and U138-MG GBM cell lines using MTT assays to determine the IC50 values of the compounds. Results: Among the tested compounds, 4u (IC50 = 7.96 μM), 4t (IC50 = 10.48 μM), 4m (IC50 = 4.20 μM), and 4q (IC50 = 8.00 μM) demonstrated significant antiproliferative effects against both the U87-MG and U138-MG cell lines. These compounds exhibited markedly higher efficacy compared to temozolomide (TMZ), which showed IC50 values of 92.90 μM and 93.09 μM for U87-MG and U138-MG, respectively. Molecular docking and dynamics studies confirmed strong interactions between the compounds and VEGFR2 kinase, supporting their substantial anti-cancer activity. Conclusions: This study highlights the promising potential of 3,4-dihydroquinolin-2(1H)-one analogues, particularly 4m, 4q, 4t, and 4u, as VEGFR2-targeting therapeutic agents for GBM treatment. Further detailed research is warranted to validate and expand upon these findings.
Abstract: A library of imidazo[1,2-a]pyridine-appended chalcones were synthesized and characterized using 1H NMR,13C NMR and HRMS. The synthesized analogs were screened for their antikinetoplastid activity against Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. The analogs were also tested for their cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all screened derivatives, (E)-N-(4-(3-(2-chlorophenyl)acryloyl)phenyl)imidazo[1,2-a]pyridine-2-carboxamide was found to be the most active against T. cruzi and T. b. brucei exhibiting IC50 values of 8.5 and 1.35 μM, resp. Against T. b. rhodesiense, (E)-N-(4-(3-(4-bromophenyl)acryloyl)phenyl)imidazo[1,2-a]pyridine-2-carboxamide was found to be the most active with an IC50 value of 1.13 μM. All synthesized active analogs were found to be non-cytotoxic against MRC-5 and PMM with selectivity indexes of up to more than 50.
Abstract: Heteroatom-based olefinating reagents (e.g., organic phosphonates, sulfonates, etc.) are used to transform carbonyl compounds into alkenes, and their mechanism of action involves aldol-type addition, cyclization, and fragmentation of four-membered ring intermediates. We have developed an analogous process using ethyl 1,1,1,3,3,3-hexafluoroisopropyl methylmalonate, which converts electrophilic aryl aldehydes into α-methylcinnamates in up to 70% yield. The reaction plausibly proceeds through the formation of β-lactone that spontaneously decarboxylates under the reaction conditions. The results shed light on the Knoevenagel–Doebner olefination, for which decarboxylative anti-fragmentation of aldol-type adducts is usually considered.
Abstract: Herein we report the synthesis of novel compounds inspired by the antimicrobial activities of nitroazole and thiazolidin-4-one based compounds reported in the literature. Target compounds were investigated in?vitro for antitubercular, antibacterial, antifungal, and overt cell toxicity properties. All compounds exhibited potent antitubercular activity. Most compounds exhibited low micromolar activity against S. aureus and C. albicans with no overt cell toxicity against HEK-293 cells nor haemolysis against human red blood cells. Notably, compound 3b exhibited low to sub-micromolar activities against Mtb, MRSA, and C. albicans. 3b showed superior activity (0.25?μg/ml) against MRSA compared to vancomycin (1?μg/ml).
* 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.
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 48, p. 11465 - 11469
2
[ 624-45-3 ]
[ 104-88-1 ]
[ 73257-49-5 ]
Yield
Reaction Conditions
Operation in experiment
84%
With ammonium acetate In neat (no solvent) at 55℃; for 3 h; Green chemistry
General procedure: Polyhydroquinolines and DihydropyridinesA mixture of aldehyde (1 mmol), β-dicarbonyl compound (1or 2 mmol), NH4OAc (2.5 mmol), dimedone (1 mmol, whenused), and SBA-15/NHSO3H (5 molpercent) was stirred at 55 °C.After complete disappearance of starting material asindicated by TLC, the resulting mixture was diluted with hotEtOAc (10 mL) and filtered. The catalyst was completelyrecovered from the residue
With iron supported on copper/Zeolite Socony Mobil-5 nanocatalyst In water at 20℃; Sonication
General procedure: In a typical experiment, aromatic aldehyde (1 mmol), bketoester(2 mmol), ammonium acetate (1 mmol), and Fe-Cu/ZSM-5 (3 wtpercent) in 2 ml water were introduced in a 20-mL heavy-walled pear-shaped two-necked flask with nonstandard-tapered outer joint. The flask was attached to a12-mm tip diameter probe, and the reaction mixture was sonicated at ambient temperature at 20 percent power of the processor. After completion of the reaction (monitored byTLC, within 5–8 min), the solid product was filtered,washed with water and ethanol, dried, and recrystallized from ethanol. The supported reagent was washed thrice with water and ethanol and dried under vacuum before reuse.
Reference：
[1] Journal of the Iranian Chemical Society, 2016, vol. 13, # 2, p. 267 - 277
4
[ 104-88-1 ]
[ 105-45-3 ]
[ 73257-49-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 80℃; for 0.3 h;
General procedure: A mixture of the alkyl or aryl aldehyde (1 mmol), -dicarbonyl(2 mmol) and ammonium acetate (1.5 mmol) in the presence ofFe3O4NPs (0.024 g, equal to 10 molpercent) was heated at 80C, withstirring. The progress of the reaction was monitored by TLC (elu-ent: EtOAc:n-hexane). After completion of the reaction, the mixturewas cooled to room temperature and then ethanol was added tothe resulting mixture and separated Fe3O4NPs by a normal mag-net. After evaporation of solvent, the solid product was filtered andrecrystallized from ethanol to give the pure products in 72–95percentyields based on the starting aldehyde.
95%
With C23H3BF16N2O; ammonium acetate In toluene at 100℃; for 10 h;
In a 100 mL single-necked flask, 0.01 molpercent of Lewis acid-base bifunctional catalyst I was added (where Rf = CF3R1,R2, R3, R4, R5, R6 = F), 0.1 mol of p-chlorobenzaldehyde (R7 = 4-Cl-Ph), 0.1 mol of methyl acetoacetate (R8 = Me;Me), 0.1 mol of ammonium acetate, 10 mL of toluene, and the reaction was stirred at 100 ° C for 10 hours. TLC followed the reaction to complete the reaction. anti-The yield of the product II (R7 = 4-Cl-Ph; R8 = Me; R9 = Me) was 95percent; the catalyst system was reused 10 timesAfter its catalytic performance did not decline
94%
for 2.25 h; Heating; Green chemistry
General procedure: A mixture of aldehyde 1 (1 mmol), 1,3-dicarbonyl compound 2 (2 mmol), and nitrogen source 3 (3 mmol) were mixed and heated in the presence of a low-melting sugar mixture.The progress of the reaction was monitored by thin-layer chromatography (TLC) using n-hexane–ethyl acetate (7:3) as the solvent system. The Rf values of the product spots ranged from 0.5 to 0.6. After completion of the reaction, water was added to the reaction mixture to obtain the solid product as a precipitate. In cases where the product was obtained as a melt, several washings with water followed by bicarbonate solution gave crystalline products. The solids were filtered and washed with cold water. In most of the cases, the product obtained was pure, and when impure, the product was recrystallized from hot ethanol. Further two products were obtained as oils (Table 5, entries 4w and 4x). These products were extracted with ethyl acetate and dried over anhydrous Na2SO4. Evaporation of the solvent gave the pure product as an oil.
91%
at 100℃; for 0.25 h; Green chemistry
General procedure: To a glassy reactor equipped with a magnetic stir bar, amixture of aromatic aldehyde (1.0 mmol), β-keto ester(2 mmol), ammonium acetate (1.5 mmol) and n-Fe3O4(at)ZrO2/HPW (0.003 g, 15 mol percent) was added. The reactorwas put in an oil bath with the temperature of 100 °C andthe reaction was carried out under solvent-free condition.The progress of the reaction was monitored using TLCplates. When the reaction was completed, the mixture wasallowed to cool to room temperature. Afterwards, the mixturewas triturated with 5mL ethyl acetate and the catalystwas separated by the help of an external magnet. Then thesolvent was evaporated and the crude product was recrystallizedfrom EtOH/H2O to offer the pure product.
90%
With uranyl nitrate hexahydrate; ammonium acetate In ethanol at 20℃; for 0.416667 h; Sonication
General procedure: To a solution of aldehyde (1.0 mmol), ethyl/methyl acetoacetate/acetylacetone (2.0 mmol) and ammonium acetate (1.0 mmol) in ethanol (3 mL), uranyl nitrate (10 molpercent) was added and the resultant reaction mixture was sonicated at room temperature for the required time (Table 1). The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into crushed ice. The obtained solid was filtered, washed thoroughly with water, dried, and purified by recrystallisation in ethanol.
Reference：
[1] RSC Advances, 2014, vol. 4, # 100, p. 56658 - 56664
[2] Tetrahedron Letters, 2010, vol. 51, # 8, p. 1187 - 1189
[3] Advanced Synthesis and Catalysis, 2012, vol. 354, # 10, p. 2001 - 2008
[4] Journal of Molecular Catalysis A: Chemical, 2014, vol. 382, p. 99 - 105
[5] Patent: CN107141249, 2017, A, . Location in patent: Paragraph 0114; 0115
[6] Synthetic Communications, 2016, vol. 46, # 24, p. 1989 - 1998
[7] RSC Advances, 2014, vol. 4, # 21, p. 10514 - 10518
[8] Journal of the Indian Chemical Society, 2009, vol. 86, # 9, p. 996 - 1000
[9] New Journal of Chemistry, 2018, vol. 42, # 15, p. 12539 - 12548
[10] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 3, p. 737 - 739
[11] Catalysis Letters, 2017, vol. 147, # 6, p. 1551 - 1566
[12] Chemical Communications, 2011, vol. 47, # 32, p. 9230 - 9232
[13] Research on Chemical Intermediates, 2015, vol. 41, # 9, p. 6877 - 6883
[14] Journal of the Chinese Chemical Society, 2016, vol. 63, # 4, p. 336 - 344
[15] Synthesis, 2007, # 18, p. 2835 - 2838
[16] Organic Preparations and Procedures International, 2012, vol. 44, # 2, p. 153 - 158
[17] Synthetic Communications, 2004, vol. 34, # 23, p. 4349 - 4357
[18] Synthetic Communications, 2009, vol. 39, # 11, p. 1957 - 1965
5
[ 105025-71-6 ]
[ 104-88-1 ]
[ 73257-49-5 ]
Reference：
[1] Journal of Materials Chemistry A, 2013, vol. 1, # 37, p. 11210 - 11220
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;
Example 2) l-MethyI-lH-pyrazoIe-3-sulfonic acid (4-chloro-benzyl)-(2-ethyl-l- oxo-1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-amide (METHOD B)i) 7-Benzylamino-3,4-dihydro-2H-isoquinolin-l-one Sodium triacetoxyborohydride (1.29 g, 6.16 mmol) was added to a stirred solution of 7-amino-3,4-dihydro-2H-isoquinolin-l-one (500 mg, 3.08 mmol), 4- chlorobenzaldehyde (431 mg, 3.0S mmol) and acetic acid (183 mul, 3.08 mmol) in anhydrous dichloromethane (25 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (50% ethyl acetate in dichloromethane) to yield the title compound as a pale yellow solid (287 mg, 16%). HPLC retention time 4.09min. Mass spectrum (ES+) m/z 287 (M+H).
5-(4-chlorobenzylamino)-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44 mg
With sodium tris(acetoxy)borohydride; trifluoroacetic acid; In isopropyl alcohol; at 20 - 70℃; for 18h;
A suspension of 5-amino-[1 ,3,4]thiadiazole-2-carboxylic acid ethyl ester (0.30 g, 1 .75 mmol), TFA (0.27 mL, 3.50 mmol), 4-chlorobenzaldehyde (0.27 g, 1 .93 mmol) and sodium triacetoxyborohydride (0.45 g, 2.10 mmol) in isopropanol (3.5 mL) was stirred at room temperature for 2 hours and then at 70°C for 1 6 hours. After this time the reaction mixture wasconcentrated under reduced pressure and purified by flash column chromatography, eluting with EtOAc/cyclohexane (0-50percent) to afford the title compound (44 mg). LCMS method: Method 3, RT: 4.81 mm, Ml: 298 [M+1] 1H NMR (500 MHz, CDCI3) O 7.32 (d, 2H), 7.29 (d, 2H), 4.53 (5, 2H), 4.41 (q, 2H), 1 .39 (t, 3H)
(+)-di-isopropyl 2-((4-chlorophenyl)((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione; In neat liquid; at 50℃; for 48h;
General procedure: Reactions were carried out with <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> 1 (0.50 mmol), aldehyde 2 (0.50 mmol) and malonate 3 (5 mmol) in the presence of catalyst III or IV (10 molpercent) at 50 °C and stirred for 48h. After completion of the reaction (as observed by TLC), the crude product was purified by preparative TLC (GF254 silica gel: hexane/EtOAc = 7/1), giving the target chiral product
(-)-di-isopropyl 2-((4-chlorophenyl)((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With quinine; In neat liquid; at 50℃; for 48h;
General procedure: Reactions were carried out with <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> 1 (0.50 mmol), aldehyde 2 (0.50 mmol) and malonate 3 (5 mmol) in the presence of catalyst III or IV (10 molpercent) at 50 °C and stirred for 48h. After completion of the reaction (as observed by TLC), the crude product was purified by preparative TLC (GF254 silica gel: hexane/EtOAc = 7/1), giving the target chiral product
(+)-diethyl 2-((4-chlorophenyl)((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione; In neat liquid; at 50℃; for 48h;
General procedure: Reactions were carried out with <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> 1 (0.50 mmol), aldehyde 2 (0.50 mmol) and malonate 3 (5 mmol) in the presence of catalyst III or IV (10 molpercent) at 50 °C and stirred for 48h. After completion of the reaction (as observed by TLC), the crude product was purified by preparative TLC (GF254 silica gel: hexane/EtOAc = 7/1), giving the target chiral product
(-)-diethyl 2-((4-chlorophenyl)((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With quinine; In neat liquid; at 50℃; for 48h;
General procedure: Reactions were carried out with <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> 1 (0.50 mmol), aldehyde 2 (0.50 mmol) and malonate 3 (5 mmol) in the presence of catalyst III or IV (10 molpercent) at 50 °C and stirred for 48h. After completion of the reaction (as observed by TLC), the crude product was purified by preparative TLC (GF254 silica gel: hexane/EtOAc = 7/1), giving the target chiral product
(+)-dimethyl 2-((4-chlorophenyl)((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl))((1S,2S,4S,5R-5-vinylquinuclidine-2-yl)methyl)amino)cyclobutan-3-ene-1,2-dione; In neat liquid; at 50℃; for 48h;
General procedure: Reactions were carried out with <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> 1 (0.50 mmol), aldehyde 2 (0.50 mmol) and malonate 3 (5 mmol) in the presence of catalyst III or IV (10 molpercent) at 50 °C and stirred for 48h. After completion of the reaction (as observed by TLC), the crude product was purified by preparative TLC (GF254 silica gel: hexane/EtOAc = 7/1), giving the target chiral product
(-)-dimethyl 2-((4-chlorophenyl)((4-(pyridin-3-yl)pyrimidin-2-yl)amino)methyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With quinine; In neat liquid; at 50℃; for 48h;
General procedure: Reactions were carried out with <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> 1 (0.50 mmol), aldehyde 2 (0.50 mmol) and malonate 3 (5 mmol) in the presence of catalyst III or IV (10 molpercent) at 50 °C and stirred for 48h. After completion of the reaction (as observed by TLC), the crude product was purified by preparative TLC (GF254 silica gel: hexane/EtOAc = 7/1), giving the target chiral product
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-One Analogues as Potential VEGFR2 Inhibitors in Glioblastoma Multiforme.png)
