A sequential Ugi‐click reactions approach for generation of novel hybrid amides/triazole‐sulfonamide as <scp>VEGFR</scp> ‐2 inhibitors targeting <scp>NSCLC</scp> and triple‐negative breast cancer

Abstract

Abstract This study rationally designed and synthesized a library of flexible Ugi‐Alkyne bis‐amides and a sequential Ugi‐Click reactions approach for the generation of novel hybrids amides/triazole‐sulfonamide as possible VEGFR‐2 inhibitors and apoptosis‐inducing candidates. Several promising hits were identified in the cytotoxicity evaluation against A549, MDA‐MB‐231, and normal lung epithelial BEAS‐2 B cells. Compound 7 exhibited the highest selectivity index (SI = 6.7 for MDA‐MB‐231; SI = 8.6 for A549) and superior potency to Sorafenib. Interestingly, compound 10 showed the most potent VEGFR‐2 inhibition with an IC 50 value of 0.084 μM, comparable to Sorafenib (IC 50 = 0.075 μM). In both cancer cell lines, compounds 6 , 7, 10 , 12 , and 23 markedly increased the tumor‐suppressive microRNAs miR‐200c and miR‐132 while downregulating the carcinogenic markers c‐Myc, CD44, CD133, VEGF, and TGF. Compounds 7 , 12 , and 23 showed the strongest impacts. Additionally, compounds 12 and 23 significantly raised the activity of caspase‐3 and caspase‐9, indicating the activation of apoptosis. Their substantial inhibitory potential was confirmed by VEGFR‐2 kinase assay and molecular docking, which further clarified important binding interactions, especially with hinge residue Cys919 and gatekeeper residues Glu885 and Asp1046. Overall, these results showed that the Ugi‐derived diamides, particularly compound 7 , are prospective anticancer leads that influence apoptosis, metastasis‐related indicators, and angiogenesis via miRNA‐associated pathways.