The online version contains supplementary material available at 10.1038/s41598-026-35429-1.

Background/Objectives: Cancer remains one of the most significant challenges in modern medicine, requiring the continuous development of novel molecular scaffolds with anticancer potential that act through multiple pathways. Heterocyclic compounds incorporating indole, triazole, oxadiazole, and thiadiazine motifs have attracted considerable attention due to their diverse pharmacological activities. This study aimed to design, synthesize, and evaluate new hybrid heterocyclic systems, including 1,2,4-triazole, 1,3,4-oxadiazole, and thiadiazine motifs, targeting liver and breast cancer. Methods: A series of indolyl-based heterocyclic compounds was synthesized using efficient and environmentally friendly protocols. Indolyl-triazol-thiadiazin-6-ol 5 was prepared via solvent-free fusion of esters 2 and 3 or the corresponding acid 4. Oxadiazole derivatives were produced by reacting hydrazide intermediates with carbon disulfide. Triazole derivatives were synthesized via cylization of thiosemicarbazide 9 in aqueous KOH (4.0 N). Structural characterization was performed using Fourier Transform InfraRed (FTIR), ¹H and ¹³C NMR spectroscopy, and electron impact mass spectrometry (EIMS). Cytotoxic activity was evaluated against liver and breast cancer cell lines, and VEGFR-2 kinase inhibition was assessed for selected derivatives. Results: The synthesized compounds demonstrated notable cytotoxicity activity, with compounds 4, 5, and 9 exhibiting IC₅₀ values in the low micromolar range. Enzymatic assays revealed that compounds 4 and 9 showed strong VEGFR-2 inhibition (97.9% and 96.4%, respectively), indicating apoptosis-inducing effects. Conclusions: The synthesized indolyl-based hybrid heterocycles represent a promising chemotype with in vitro cytotoxic activity and VEGFR-2 inhibitory effects, supporting further investigation, optimization, and mechanistic studies to evaluate their potential lead for anticancer drug development.