New Niflumic Acid Derivatives as EGFR Inhibitors : Design, Synthesis, In silico Studies, and Anti-proliferative Assessment
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
BACKGROUND: 1,3,4-oxadizole and pyrazole derivatives are very important scaffolds for medicinal chemistry. A literature survey revealed that they possess a wide spectrum of biological activities including anti-inflammatory and antitumor effects.
OBJECTIVES: To describe the synthesis and evaluation of two classes of new niflumic acid (NF) derivatives, the 1,3,4-oxadizole derivatives (compounds 3 and (4A-E) and pyrazole derivatives (compounds 5 and 6), as EGFR tyrosine kinase inhibitors in silico and in vitro.
METHODS: The designed compounds were synthesized using conventional organic synthesis methods. The antitumor activities of the new NF derivatives against HepG2 hepatocellular carcinoma and A549 non-small cell lung cancer cell lines were assessed in vitro via MTT assay, flow cytometry, RT-PCR, as well as via molecular docking studies.
RESULTS: The cytotoxicity results indicated that the newly synthesized NF derivatives were cytotoxic against the two cancer cell lines, with compound 6 being the most cytotoxic, achieving the lowest IC50 concentration. Furthermore, compound 6 targeted EGFR tyrosine kinase leading to cell cycle arrest at the G2/M cell cycle phase and induction of apoptosis. The in vitro biological investigation results matched those of the molecular docking analysis. In conclusion, the new NF derivatives, specifically compound 6, exhibited favorable pharmacokinetic features and are promising EGFR tyrosine kinase inhibitors.
CONCLUSION: A series of niflumic acid derivatives (3, 4A-E, 5, and 6) were successfully created, and FT-IR, <sup>1</sub>H, <sub>13</sub>CNMR, and HRMS were used to confirm their chemical structures. According to molecular docking studies, compounds 3, 5, and 6 have the highest docking scores (ΔG), and most tested compounds have a good pharmacokinetic profile. Results of compound 6 in vitro antitumor activities showed that it is a promising EGFR tyrosine kinase inhibitor.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
Medicinal chemistry (Shariqah (United Arab Emirates)) - 19(2023), 5 vom: 19., Seite 445-459 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yaseen, Yahya S [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.05.2023 Date Revised 16.05.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.2174/1573406419666221219144804 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Yaseen, Yahya S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a New Niflumic Acid Derivatives as EGFR Inhibitors |b Design, Synthesis, In silico Studies, and Anti-proliferative Assessment |
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| 500 | |a Date Revised 16.05.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a BACKGROUND: 1,3,4-oxadizole and pyrazole derivatives are very important scaffolds for medicinal chemistry. A literature survey revealed that they possess a wide spectrum of biological activities including anti-inflammatory and antitumor effects | ||
| 520 | |a OBJECTIVES: To describe the synthesis and evaluation of two classes of new niflumic acid (NF) derivatives, the 1,3,4-oxadizole derivatives (compounds 3 and (4A-E) and pyrazole derivatives (compounds 5 and 6), as EGFR tyrosine kinase inhibitors in silico and in vitro | ||
| 520 | |a METHODS: The designed compounds were synthesized using conventional organic synthesis methods. The antitumor activities of the new NF derivatives against HepG2 hepatocellular carcinoma and A549 non-small cell lung cancer cell lines were assessed in vitro via MTT assay, flow cytometry, RT-PCR, as well as via molecular docking studies | ||
| 520 | |a RESULTS: The cytotoxicity results indicated that the newly synthesized NF derivatives were cytotoxic against the two cancer cell lines, with compound 6 being the most cytotoxic, achieving the lowest IC50 concentration. Furthermore, compound 6 targeted EGFR tyrosine kinase leading to cell cycle arrest at the G2/M cell cycle phase and induction of apoptosis. The in vitro biological investigation results matched those of the molecular docking analysis. In conclusion, the new NF derivatives, specifically compound 6, exhibited favorable pharmacokinetic features and are promising EGFR tyrosine kinase inhibitors | ||
| 520 | |a CONCLUSION: A series of niflumic acid derivatives (3, 4A-E, 5, and 6) were successfully created, and FT-IR, <sup>1</sub>H, <sub>13</sub>CNMR, and HRMS were used to confirm their chemical structures. According to molecular docking studies, compounds 3, 5, and 6 have the highest docking scores (ΔG), and most tested compounds have a good pharmacokinetic profile. Results of compound 6 in vitro antitumor activities showed that it is a promising EGFR tyrosine kinase inhibitor | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ADMET | |
| 650 | 4 | |a EGFR kinase activity | |
| 650 | 4 | |a apoptosis | |
| 650 | 4 | |a cytotoxicity | |
| 650 | 4 | |a oxadiazole | |
| 650 | 4 | |a pyrazole | |
| 650 | 7 | |a Niflumic Acid |2 NLM | |
| 650 | 7 | |a 4U5MP5IUD8 |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a ErbB Receptors |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a EGFR protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 700 | 1 | |a Mahmood, Ammar A R |e verfasserin |4 aut | |
| 700 | 1 | |a Abbas, Ali H |e verfasserin |4 aut | |
| 700 | 1 | |a Shihab, Wurood A |e verfasserin |4 aut | |
| 700 | 1 | |a Tahtamouni, Lubna H |e verfasserin |4 aut | |
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