Novel <i>N</i>-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study
A series of eleven new <i>N</i>-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and...
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2025-07-01
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| author | Samar A. Abubshait |
| author_facet | Samar A. Abubshait |
| author_sort | Samar A. Abubshait |
| collection | DOAJ |
| description | A series of eleven new <i>N</i>-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and hydrophile characters to a quinoxaline ring system. 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide was produced in a two-step reaction of methyl 3-(3-oxo-3,4-dihydroquinoxalin-2-yl) propanoate with benzyl chloride followed by the hydrazinolysis of the corresponding ester. The antiproliferative activity of the compounds was tested in various cancer cell lines, including PC-3, Hela, HCT-116, and MCF-7; they showed a wide spectrum of activity for most of the tested compounds. Compound <b>6k</b> exhibited the highest activity, which was comparable to that of doxorubicin, with IC<sub>50</sub> (µM) values of 12.17 ± 0.9, 9.46 ± 0.7, 10.88 ± 0.8, and 6.93 ± 0.4 µM compared to 8.87 ± 0.6, 5.57 ± 0.4, 5.23 ± 0.3, and 4.17 ± 0.2 µM for doxorubicin against Hela, HCT-116, and MCF-7, respectively. The in silico mechanistic study revealed the inhibition of HDAC-6 through the binding of the unique zinc finger ubiquitin-binding domain (HDAC6 Zf-UBD). The docking results showed a specific binding pattern that emphasized the crucial role of the quinoxaline ring and its substituents. The newly developed derivatives were evaluated for antitumor effects against four cancer cell lines PC-3, HeLa, HCT-116, and MCF-7. This research led to the identification of a quinoxaline-based scaffold exhibiting broad-spectrum antiproliferative activity and a distinct mechanism involving binding to HDAC6 Zf-UBD. The findings highlight its potential for further optimization and preclinical studies to support future anticancer drug development. |
| format | Article |
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| institution | Matheson Library |
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| language | English |
| publishDate | 2025-07-01 |
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| series | Molecules |
| spelling | doaj-art-c1b7a98d45a547e098727e61c9ec2bee2025-07-25T13:32:05ZengMDPI AGMolecules1420-30492025-07-013014302510.3390/molecules30143025Novel <i>N</i>-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic StudySamar A. Abubshait0Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi ArabiaA series of eleven new <i>N</i>-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and hydrophile characters to a quinoxaline ring system. 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide was produced in a two-step reaction of methyl 3-(3-oxo-3,4-dihydroquinoxalin-2-yl) propanoate with benzyl chloride followed by the hydrazinolysis of the corresponding ester. The antiproliferative activity of the compounds was tested in various cancer cell lines, including PC-3, Hela, HCT-116, and MCF-7; they showed a wide spectrum of activity for most of the tested compounds. Compound <b>6k</b> exhibited the highest activity, which was comparable to that of doxorubicin, with IC<sub>50</sub> (µM) values of 12.17 ± 0.9, 9.46 ± 0.7, 10.88 ± 0.8, and 6.93 ± 0.4 µM compared to 8.87 ± 0.6, 5.57 ± 0.4, 5.23 ± 0.3, and 4.17 ± 0.2 µM for doxorubicin against Hela, HCT-116, and MCF-7, respectively. The in silico mechanistic study revealed the inhibition of HDAC-6 through the binding of the unique zinc finger ubiquitin-binding domain (HDAC6 Zf-UBD). The docking results showed a specific binding pattern that emphasized the crucial role of the quinoxaline ring and its substituents. The newly developed derivatives were evaluated for antitumor effects against four cancer cell lines PC-3, HeLa, HCT-116, and MCF-7. This research led to the identification of a quinoxaline-based scaffold exhibiting broad-spectrum antiproliferative activity and a distinct mechanism involving binding to HDAC6 Zf-UBD. The findings highlight its potential for further optimization and preclinical studies to support future anticancer drug development.https://www.mdpi.com/1420-3049/30/14/3025benzyloxyquinoxalineazide couplingprimary and secondary aminesanticancer |
| spellingShingle | Samar A. Abubshait Novel <i>N</i>-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study Molecules benzyloxyquinoxaline azide coupling primary and secondary amines anticancer |
| title | Novel <i>N</i>-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study |
| title_full | Novel <i>N</i>-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study |
| title_fullStr | Novel <i>N</i>-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study |
| title_full_unstemmed | Novel <i>N</i>-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study |
| title_short | Novel <i>N</i>-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study |
| title_sort | novel i n i alkyl 3 3 benzyloxyquinoxalin 2 yl propanamides as antiproliferative agents design synthesis in vitro testing and in silico mechanistic study |
| topic | benzyloxyquinoxaline azide coupling primary and secondary amines anticancer |
| url | https://www.mdpi.com/1420-3049/30/14/3025 |
| work_keys_str_mv | AT samaraabubshait novelinialkyl33benzyloxyquinoxalin2ylpropanamidesasantiproliferativeagentsdesignsynthesisinvitrotestingandinsilicomechanisticstudy |