Convenient syntheses of methyl 2-[2-(3-acetyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetamido] alkanoates and their O-regioisomers

Ali, Ibrahim A. I.; Fathalla, Walid; Rayes, S. M. El

doi:10.3998/ark.5550190.0009.d20

Cited by 13 publications

(5 citation statements)

References 14 publications

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“…Our research team quickly discovered that chemoselective alkylation of amides and thioamides could be regulated. − We agreed to extend our results to the structure modification of 2-phenyl-2,3-dihydrophthalazine-1,4-dione ( 1 ), our model heterocyclic amide, as a follow-up to these studies. The single O-substituted result of the reaction of model ambient nucleophile 1 with ethyl chloroacetate in acetone in the presence of K 2 CO 3 under reflux for 12 h was (4-oxo-3-phenyl-3,4-dihydro-phthalazin-1-yloxy)acetic acid ethyl ester ( 2 ).…”

Section: Resultssupporting

confidence: 92%

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Synthesis of Novel Phthalazinedione-Based Derivatives with Promising Cytotoxic, Anti-bacterial, and Molecular Docking Studies as VEGFR2 Inhibitors

et al. 2022

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The parent ester methyl-3-[2-(4-oxo-3-phenyl-3,4-dihydro-phthalazin-1-yloxy)-acetylamino] has 18 compounds. The starting material for alkanoates, their corresponding hydrazides, hydrazones, and dipeptides were produced by chemoselective O-alkylation of 2-phenyl-2,3-dihydrophthalazine-1,4-dione with ethyl chloroacetate(4-oxo-3-phenyl-3,4-dihydro-phthalazin-1-yloxy) acetic acid methyl ester. The starting ester was hydrazinolyzed, then azide coupled with amino acid ester hydrochloride to produce several parent esters, and then hydrazinolyzed to produce parent hydrazides. These hydrazides were used to make a series of dipeptides by reacting them with amino acid ester hydrochloride under azide coupling conditions, and they were also condensed with a number of aldehydes to make the hydrazones. These derivatives were subjected to cytotoxicity against HCT-116 and MDA-MB-231 cells and anti-bacterial and molecular docking studies. Results indicated that the tested compounds, especially 7c and 8b with the phenyl phthalazinone moieties, had promising cytotoxicity against the HCT-116 cells with IC 50 values of 1.36 and 2.34 μM, respectively. Additionally, the promising compounds 7c and 8b exhibited poor cytotoxicity against WISH cells with much higher IC 50 values, so they were safe against normal cells. Compound 8c exhibited potent anti-bacterial activity with inhibition zones of 12 and 11 mm against Staphylococcus aureus and Escherichia coli , respectively. The molecular docking results of compounds 7c and 8b revealed a good binding disposition and the ligand–receptor interactions like the co-crystallized ligand of the VEGFR2 protein, which may be the proposed mode of action. Finally, compounds 7c and 8b exhibited good ADME pharmacokinetics with good drug-likeness parameters. Hence, detailed studies for the mechanism of action of such compounds are highly recommended for the development of new potent anti-cancer and anti-bacterial agents.

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Section: Resultssupporting

confidence: 92%

“…Methyl {2- 13 C NMR (100.0 MHz, CDCl 3 ), δ, ppm: 41. 1,42.6,52.4,65.6 (OCH 2 ),123.2,123.8,124.9,127.2,128.0,128.6,129.9,132.6,133.5,141.6,148.5,158.3 (C=O) ,59.43;H,4.75;N,13.20.…”

Section: Dihydrophthalazin-1-yloxy)-acetylamino]-pentanoate (5c)mentioning

confidence: 99%

Synthesis of Novel Phthalazinedione-Based Derivatives with Promising Cytotoxic, Anti-bacterial, and Molecular Docking Studies as VEGFR2 Inhibitors

et al. 2022

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“…Our experience in the chemoselective alkylation at nitrogen or sulfur of heterocyclic thioamides and chemoselective alkylation at nitrogen or oxygen of heterocyclic amides causes a dramatic change in the aromatic proton and carbon NMR patterns. 20−38 Furthermore, the expected N-substituted ester methyl 3-(3-phenyl-2-thioxoquinoxalin-1(2 H )-yl)propanoate should have an extra down fielded carbon signal of about 178 ppm for the C=S group and a higher chemical shift of about 42–45 ppm for NCH 2 . 20,21…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the 13 C NMR spectrum of 7 displays two signals at 33.8 and 172.4 ppm for SCH 2 and ester carbonyl groups, respectively, and also aromatic carbons at 154.7, 153.4, 141.5, 139.4, 137.2, 129.8, 129.7, 129.2, 129.0, 128.5, 128.3, and 127.6 ppm. Our experience in the chemoselective alkylation at nitrogen or sulfur of heterocyclic thioamides and chemoselective alkylation at nitrogen or oxygen of heterocyclic amides causes a dramatic change in the aromatic proton and carbon NMR patterns. − Furthermore, the expected N-substituted ester methyl 3-(3-phenyl-2-thioxoquinoxalin-1(2 H )-yl)propanoate should have an extra down fielded carbon signal of about 178 ppm for the CS group and a higher chemical shift of about 42–45 ppm for NCH 2 . , …”

Section: Resultsmentioning

confidence: 99%

Convenient Synthesis and Anticancer Activity of Methyl 2-[3-(3-Phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and N-Alkyl 3-((3-Phenyl-quinoxalin-2-yl)sulfanyl)propanamides

et al. 2019

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A series of methyl 2-[3-(3-phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and their corresponding hydrazides and N-alkyl 3-((3-phenylquinoxalin-2-yl)sulfanyl)propanamides were prepared on the basis of the chemoselective Michael reaction of acrylic acid with the parent substrate 3-phenylquinoxaline-2(1H)-thione. The parent thione was produced by a convenient novel thiation method from the corresponding 3-phenylquinoxalin-2(1H)-one. The chemical structures of the newly synthesized compounds were confirmed by elemental analyses, 1H and 13C NMR. The antiproliferative activity of the synthesized compounds was tested against human HCT-116 and MCF-7 cell lines. Out of 25 screened derivatives, 10 active compounds exhibited IC50’s in the range 1.9–7.52 μg/mL on the HCT-116, and 17 active compounds exhibited IC50’s in the range 2.3–6.62 μg/mL on the MCF-7 cell lines compared to the reference drug doxorubicin (IC50 3.23 μg/mL). The structure–activity relationship of the tested compounds was studied through their binding affinity to the human thymidylate synthase allosteric site in silico using molecular docking and proved the quinoxaline ring as a suitable scaffold carrying a peptidomimetic side chain in position 3.

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“…Chemoselective reactions of heterocyclic amides with electrophiles were extensively investigated by our research group to afford either N-substituted, O-substituted, or a mixture of both. These results were used to structure and modify several heterocyclic systems and were supported by theoretical DFT calculations to predict the site of alkylation. − To find more promising quinoline derivatives for biological evaluation, we now report the preparation of N -alkyl-3-[2-oxoquinolin-1(2 H )-yl]propanamide and related compounds based on the chemoselective reaction of 2-quinolinone with methyl acrylate under Michael reaction conditions and investigate their activity as cytotoxic agents, highlighting the effective molecular target.…”

Section: Introductionmentioning

confidence: 95%

Synthesis of N-Alkyl-3-[2-oxoquinolin-1(2H)-yl]propanoic Acid Derivatives and Related Compounds: Cytotoxicity and EGFR Inhibition of Some Propanamide Derivatives

El Rayes,

Ali,

Fathalla

et al. 2024

ACS Omega

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A series of 20 new structure-modified quinolin-2-one derivatives were prepared for biological evaluation. This was successfully achieved based on chemoselective reactions of heterocyclic amides with acrylic acid derivatives, which gave 3-[2oxoquinolin-1-(2H)-yl] propanoic acid derivatives (N-substitution via a unique behavior). The ester was reacted with hydrazine to afford the corresponding hydrazide. Both the corresponding ester and hydrazide were used as building blocks to modify the quinolone structure and give N-hydroxyl propanamides, oxadiazoles, and thiosemicarbazides. The corresponding carboxylic acid and hydrazide were used to prepare several amides: N-alkyl-3-[2-oxoquinolin-1(2H)-yl]propanamides via azide and dicyclohexyl carbodiimide coupling methods. Among derivatives, compound 9e exhibited potent cytotoxicity against MCF-7 cells with an IC 50 value of 1.32 μM compared to doxorubicin with an IC 50 value of 1.21 μM. Additionally, it caused potent EGFR inhibition by 97% with an IC 50 value of 16.89 nM compared to Erlotinib with an IC 50 value of 29.8 nM. Finally, the binding mode of compound interactions toward EGFR was highlighted using a molecular docking study; compound 9e exhibited good binding affinity with a binding energy of −17.89 kcal/mol, and it formed H-bond interactions with Met 769 as the key amino acid of interaction. Accordingly, compound 9e may be developed as an EGFR-oriented chemotherapeutic antibreast cancer agent.

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Convenient syntheses of methyl 2-[2-(3-acetyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetamido] alkanoates and their O-regioisomers

Cited by 13 publications

References 14 publications

Synthesis of Novel Phthalazinedione-Based Derivatives with Promising Cytotoxic, Anti-bacterial, and Molecular Docking Studies as VEGFR2 Inhibitors

Synthesis of Novel Phthalazinedione-Based Derivatives with Promising Cytotoxic, Anti-bacterial, and Molecular Docking Studies as VEGFR2 Inhibitors

Convenient Synthesis and Anticancer Activity of Methyl 2-[3-(3-Phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and N-Alkyl 3-((3-Phenyl-quinoxalin-2-yl)sulfanyl)propanamides

Synthesis of N-Alkyl-3-[2-oxoquinolin-1(2H)-yl]propanoic Acid Derivatives and Related Compounds: Cytotoxicity and EGFR Inhibition of Some Propanamide Derivatives

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