VEGFR-2 inhibitors and apoptosis inducers: synthesis and molecular design of new benzo<i>[g]</i>quinazolin bearing benzenesulfonamide moiety

<p>Two series of novel 4-(2-(2-(2-(substituted) hydrazinyl)-2-oxoethylthio)-4-oxobenzo[<i>g</i>]quinazolin-3(<i>4H</i>)-yl) benzenesulfonamide <b>5–17</b> and 4-(2-(2-(substituted-1<i>H</i>-pyrazol-1-yl)-2-oxoethylthio)-4-oxobenzo[<i>g</i>]quinazolin-3(4<i>H</i>)-yl) benzenesulfonamide <b>18–24</b> were synthesised from the starting material 4-(2-(2-hydrazinyl-2-oxoethylthio)-4-oxobenzo[<i>g</i>]quinazolin-3(<i>4H</i>)-yl) benzenesulfonamide <b>5,</b> to be evaluated for their inhibitory activity towards VEGFR-2. The target compounds <b>5–24,</b> were screened for their cytotoxic activity against MCF-7 breast cancer cell line and the percentage inhibition against VEGFR-2. Compounds <b>9, 20, 22</b> and <b>23</b>, showed excellent VEGFR-2 inhibitory activity with IC₅₀ ranging from 0.64 to 1.04 µm. Being the most potent, compound <b>9</b> was evaluated for its apoptotic inducer effect by studying the effect on caspase-3, it was found to increase its level. Compound <b>9</b> boosted the level of Bax and reduced the level of BCl2, compared to the control. Cell cycle analysis was conducted, compound <b>9</b> showed cell cycle arrest at G2/M phase. Moreover, mild cytotoxic effect (IC₅₀ = 29.41 µm, respectively) in normal breast cells MCF-12 A, was observed when treated with the same compound. Finally, a molecular docking study was performed to investigate the possible binding interaction inside the active site of the VEGFR-2 enzyme.</p