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

Autor: 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.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2022 Jul; Vol. 355 (7), pp. e2200048. Date of Electronic Publication: 2022 Apr 18.
DOI: 10.1002/ardp.202200048
Abstrakt: 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.)
Databáze: MEDLINE
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