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

Abstract

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.

In vitroand computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-MProinhibitors

“…The cytotoxic activity was assessed using the MTT colorimetric assay as reported previously. [58][59][60][61][62] In brief, tumour cell lines were suspended in medium at concentration 5 Â 10 4 cell/well in Corning® 96-well tissue culture plates and then incubated for 24 h. The tested compounds with concentrations ranging from 0 to 50 mg ml À1 were then added into 96-well plates (in a triplicate) to achieve different concentrations for each compound. Vehicle controls with media or 0.5% DMSO were run for each 96 well plate as a negative control.…”

Rationale design, synthesis, cytotoxicity evaluation, andin silicomechanistic studies of novel 1,2,3-triazoles with potential anticancer activity

“…Furthermore: they may show reduced side effects. Accordingly, in this work, in continuation of our recent studies on the development of new suggested anticancer agents, [29][30][31][32][33][34][35] we considered the biological significance of VEGFR-2 inhibition as an effective strategy in the management of cancer and the importance of 1,2,3-triazole, thiazole, thiazolone, and hydrazine as attractive pharmacophoric fragments in the development of chemotherapeutic agents to design a new set of 1,2,3triazole hybrids as potential anticancer agents (Fig. 2).…”