Design, synthesis, and antiproliferative properties of new 1,2,3-triazole-carboximidamide derivatives as dual EGFR/VEGFR-2 inhibitors

A new series of substituted aryl carboximidamide VIa-o was designed and synthesised. IR, 1 H NMR, 13 C NMR as well as elemental microanalysis were used to confirm the structures of the new compounds. The antiproliferative effect of the news compounds against four cancer cell lines was investigated. Com-pounds VIc, VIg, VIj, VIk, VIm, and VIo were the most potent ones with GI50 ranging from 34 to 48 nM, compared with erlotinib (GI50 of 33 nM). The utmost potent compounds were further examined for their efficacy as EGFR inhibitors, and the results showed that the tested compounds inhibited EGFR with IC50 ranging from 83 nM to 112 nM when compared to the reference erlotinib (IC50 = 80 nM). Moreover, the six most potent compounds had promising VEGFR-2 inhibitory activity, with IC50 ranging from 1.8 nM to 11.4 nM compared with sorafenib, (IC50 = 0.17 nM). The most potent VEGFR-2 inhibitors were VIc, VIk, and VIo, with IC50 2.90, 1.80, and 2.40 nM, respectively. Additionally, molecular docking simulations of the most potent compounds against EGFR and VEGFR-2 enzymes highlighted high binding affinity and active site interactions of compounds VIc, VIk, and VIo that could be shown as potential dual EGFR and VEGFR-2 inhibitors. The apoptotic mechanism displayed that the most active compound VIk showed the highest induced levels for Caspase-3 and Bax while down-regulated the anti-apoptotic Bcl-2 protein levels in the A-549 human epithelial cancer cell line. The ADME of compounds VIa-o revealed safety and good pharmacokinetic profile of active compounds.(c) 2023 Published by Elsevier B.V.

Automated summary

A new series of substituted aryl carboximidamide VIa-o was designed and synthesised, and their structures were confirmed using spectroscopy and elemental analysis. The antiproliferative effect of these compounds against four cancer cell lines was investigated, and VIc, VIg, VIj, VIk, VIm, and VIo showed the strongest activity. Molecular docking simulations revealed that VIc, VIk, and VIo exhibited high affinity and active site interactions with EGFR and VEGFR-2 enzymes, suggesting their potential as dual inhibitors. Compound VIk demonstrated the highest induced levels of apoptotic markers in A-549 cancer cells, indicating its pro-apoptotic effect. ADME studies showed that the active compounds had good safety and pharmacokinetic profiles.