New quinoxalin-2(1H)-one-derived VEGFR-2 inhibitors: Design, synthesis, in vitro anticancer evaluations, in silico ADMET, and docking studies.

التفاصيل البيبلوغرافية
العنوان:	New quinoxalin-2(1H)-one-derived VEGFR-2 inhibitors: Design, synthesis, in vitro anticancer evaluations, in silico ADMET, and docking studies.
المؤلفون:	El-Adl K; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt., Sakr HM; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt., Yousef RG; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt., Mehany ABM; Zoology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt., Abulkhair HS; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt., Eissa IH; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
المصدر:	Archiv der Pharmazie [Arch Pharm (Weinheim)] 2022 Jul; Vol. 355 (7), pp. e2200048. Date of Electronic Publication: 2022 Apr 18.
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Wiley-VCH Verlag GmbH & Co. KGaA Country of Publication: Germany NLM ID: 0330167 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-4184 (Electronic) Linking ISSN: 03656233 NLM ISO Abbreviation: Arch Pharm (Weinheim) Subsets: MEDLINE
أسماء مطبوعة:	Publication: <2005->: Weinheim Germany : Wiley-VCH Verlag GmbH & Co. KGaA Original Publication: Weinheim, Verlag Chemie GmbH.
مواضيع طبية MeSH:	Antineoplastic Agents* , Vascular Endothelial Growth Factor Receptor-2*, Angiogenesis Inhibitors/pharmacology ; Cell Proliferation ; Drug Design ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Protein Kinase Inhibitors ; Quinoxalines/pharmacology ; Sorafenib/pharmacology ; Structure-Activity Relationship ; Vascular Endothelial Growth Factor A/pharmacology
مستخلص:	More than 70% of cancer patients who are treated with chemotherapeutics do not show a durable response. As part of the global plan seeking new effective chemotherapeutics, here, we report the synthesis and in vitro and computational studies of new lenvatinib and sorafenib analog quinoxalines as vascular endothelial growth factor receptor II (VEGFR-2) tyrosine kinase inhibitors. The central quinolone and pyridine moieties of the Food and Drug Administration-approved anticancer agents lenvatinib and sorafenib were replaced with the versatile quinoxaline scaffold that has been exploited for developing potent cytotoxic agents. With some minor structural optimizations, all the other pharmacophoric features of lenvatinib and sorafenib were maintained. Accordingly, three new sets of quinoxalines were synthesized to evaluate their activity against liver, colorectal, and breast malignancies. The results obtained in the in vitro cytotoxicity evaluation study revealed the superior activity of three derivatives (20, 25, and 29) compared with that of doxorubicin and sorafenib. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling and docking of 20, 25, and 29 into the VEGFR-2 receptor were also performed. Results of in silico studies showed the potential of the designed compounds to bind effectively with a number of key residues. The obtained in vitro cytotoxic activity and ADMET profiles of compounds 20, 25, and 29 suggested that they should be subjected to further structural optimizations to develop new candidates in cancer treatment protocols. (© 2022 Deutsche Pharmazeutische Gesellschaft.)
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معلومات مُعتمدة:	None
فهرسة مساهمة:	Keywords: VEGFR-2; anticancer; lenvatinib; molecular docking; quinoxalines
المشرفين على المادة:	0 (Angiogenesis Inhibitors) 0 (Antineoplastic Agents) 0 (Protein Kinase Inhibitors) 0 (Quinoxalines) 0 (Vascular Endothelial Growth Factor A) 9ZOQ3TZI87 (Sorafenib) EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
تواريخ الأحداث:	Date Created: 20220419 Date Completed: 20220706 Latest Revision: 20220706
رمز التحديث:	20240628
DOI:	10.1002/ardp.202200048
PMID:	35437829
قاعدة البيانات:	MEDLINE

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تدمد:	1521-4184
DOI:	10.1002/ardp.202200048