Design, synthesis, SAR, in silico and in vitro evaluation of 1, 3, 4-oxadiazole derivatives against breast cancer
TL;DR
R3 emerges as a promising VEGFR2-targeted lead for further breast cancer drug development and structure-activity relationship analysis indicated that meta and para chloro substitutions enhance binding and activity, while ortho substitution reduces affinity due to steric effects.
Abstract
The 1,3,4-oxadiazole scaffold is well recognized for its anticancer potential. Based on our previous work, we designed and synthesized nine 1,3,4-oxadiazole derivatives (R1–R9) via Schiff base formation followed by cyclization. The compounds were characterized by FT-IR, ¹H NMR, and mass spectroscopy and evaluated for anticancer activity against MCF-7 breast cancer cells. Target prediction using PASS and SwissTargetPrediction indicated kinase receptors as likely targets. Owing to its central role in angiogenesis and breast cancer progression, VEGFR2 was selected for molecular docking. Docking, scoring, and binding free energy analyses showed strong affinity of the compounds within the VEGFR2 ATP binding pocket. Notably, R3 formed key interactions with GLU885, ASP1046, and LYS868 and exhibited the most favourable binding stability (− 84.42 kcal/mol). ADMET predictions suggested good gastrointestinal absorption, oral bioavailability, and acceptable toxicity, with attention warranted for solubility and blood-brain barrier penetration during optimization. In vitro evaluation using the MTT assay revealed IC₅₀ values of 8.06–17.34 µM. R3 showed the highest potency (IC₅₀ = 8.06 µM), comparable to doxorubicin. Structure-activity relationship analysis indicated that meta and para chloro substitutions enhance binding and activity, while ortho substitution reduces affinity due to steric effects. Overall, R3 emerges as a promising VEGFR2-targeted lead for further breast cancer drug development.