Utility of Aroyl isothiocyanate in Construction of Novel Heterocyclic Compounds with Anticipated Biological Activity

Abstract

VEGFR-2 inhibitors have been becoming one of the most therapeutic strategy for treatment of cancer diseases because of their critical role in preventing cancer growth and metastasis. Herein, new series of novel N-(1,3,4-thiadiazol-2-yl)furan-2-carboxamide derivatives were designed and synthesized based on the same essential pharmacophoric features of the reported VEGFR-2 inhibitors by adopting a hybridization of bioisosteric strategy. Antiproliferative activities were biologically evaluated against three human cancer cell lines (MCF-7, HCT-116 and PC-3) using MTT assay technique and doxorubicin was used as a positive control. Compounds, 6, 7, 11 and 14 were found to be significantly more potent than doxorubicin against all tested cell lines. Moreover, compounds, 6 and 11 proved to be the most active compounds with IC50 values of 6.58, 4.19, and 7.76 µM, and 6.41, 5.01, and 8.47 µM, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities. Among them, compounds, 11, 7 and 15 exhibited excellent inhibition against VEGFR-2 with IC50 values of 7.6±0.4, 9.4±0.8 and 8.2±0.4 µM, respectively, compared with pazopanib as control drug with IC50 value of 9.7±0.4 µM. Furthermore, structure-activity relationship (SAR) studies indicated the active methylene linker substituted with heteroaromatic ring enhances the antiproliferative activity. Besides, molecular docking studies were also performed and attributed the promising activity of this series to their hydrogen bonding interactions with the key amino acid residues, Glu885, Cys919 and Asp1026 and hydrophobic interactions with the VEGFR-2 binding site.