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Background  Tumor angiogenesis, essential for tumor growth and metastasis, is tightly regulated by VEGF/VEGFR and PDGF/PDGFR pathways, and therefore blocking those pathways is a promising therapeutic target. Compared to sunitinib, the C(5)-Br derivative of 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole has significantly greater in vitro activities against VEGFR-2, PDGFRβ, and tube formation.    Results and discussion  The objective of this study was to perform further structural optimization, which revealed certain new products with even more potent anti-tumor activities, both cellularly and enzymatically. Of these,  15  revealed ten- and eightfold stronger potencies against VEGFR-2 and PDGFRβ than sunitinib, respectively, and showed selectivity against HCT116 with a favorable selective index (SI > 4.27). The molecular docking results displayed that the ligand–protein binding affinity to VEGFR-2 could be enhanced by introducing a hydrogen-bond-donating (HBD) substituent at C(5) of (2-oxoindolin-3-ylidene)methylpyrrole such as  14  (C(5)-OH) and  15  (C(5)-SH).    Conclusions  Among newly synthetic compounds,  7  and  13 – 15  exhibited significant inhibitory activities against VEGFR-2 and PDGFRβ. Of these, the experimental results suggest that  15  might be a promising anti-proliferative agent.   Graphical abstract   IC 50  comparison of sunitinib,  14 , and  15  against VEGFR-2 and PDGFRβ.Electronic supplementary material  The online version of this article (doi:10.1186/s13065-017-0301-5) contains supplementary material, which is available to authorized users.

chemistry central journal

Structural optimization and evaluation of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential VEGFR-2/PDGFRβ inhibitors