Design, Synthesis and Evaluation of 5-pyridin-4-yl-2-thioxo-[1,3,4]oxadiazol-3-yl Derivatives as Anti-angiogenic Agents Targeting VEGFR-2
Ramaa Subramanian Chelakara.
Background: Angiogenesis is physiological process in embryogenesis, organ development, endometrial
vasculature in menstrual cycle and wound healing. Angiogenesis has also been associated with several pathological
conditions such as cancer, arthritis, atherosclerosis, etc. Out of the many growth factor responsible for angiogenesis,
vascular endothelial growth factor (VEGF) is one of the most important and positive regulator of angiogenesis with its
distinct specificity for vascular endothelial cells. The current work is the small efforts towards development of newer
inhibitor of angiogenesis targeting VEGFR-2.
Objective: With the view to develop inhibitors of angiogenesis, pharmacophore characteristics were used to design
aromatic/ heteroaromatic ring containing compounds. These compounds were then docked in to the active side of
VEGFR-2 with the aid of docking. They were then synthesize and spectrally characterized and carry out in-vitro and
in-vivo anti-angiogenic evaluation studies to ascertain its angiogenesis inhibition potential.
Result: 3-substituted-5-(4-pyridin-4yl)-1,3,4-oxadiazole-2-thiones designed as inhibitors of angiogenesis targeting
VEGFR2. In docking study, all the molecules showed similar way of binding with VEGFR2 as that of the cocrystallised
ligand. Compound 3i and 3j were found to be most active in the series showing good inhibition of
angiogenesis in both CAM and in zebrafish embryo assays. The compound 3i was the most active in the series with
IC50 of 0.5 μM for VEGR-2.
Conclusion: To conclude the work we have successfully designed newer inhibitors of angiogenesis targeting VEGFR-
2. These compounds were then screen and found to inhibit angiogenesis of CAM and zebrafish at dose of 1 μM.
Keywords: 3-substituted-5-(4-pyridin-4yl)-1, 3, 4-oxadiazole-2-thiones, VEGFR2, Docking, CAM assay, Zebrafish embryo.
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