ABSTRACT The present study describes the design, synthesis and in vitro biological evaluation of urea–sulfonamide hybrids as possible VEGFR‐2 inhibitors and apoptosis inducing agents against liver (HepG2) and breast (MCF‐7) cancer cells. The synthesized compounds (AS1–AS8) were characterized using FTIR, NMR, mass spectrometry, and elemental analysis and found to be structurally intact. The biological evaluation indicated that AS5 was the most effective one, with IC 50 value of 0.12 µM (MCF‐7) and 0.08 µM (HepG2), which were lower than those of reference drug Sorafenib. Compounds AS3, AS7, and AS8 were highly active in terms of growth inhibition (IC 50 < 1 µM). Molecular docking analysis identified AS4 and AS5 as VEGFR‐2 high‐affinity binders and binding to key residues such as Glu885 and Asp1046 were involved. Additionally, a number of the derivatives displayed significant inhibition of the tumor‐associated carbonic anhydrase isoforms CA IX and CA XII (Ki values ranging between 14.5 nM and 104.5 nM for CA IX and 18.6–122.7 nM for CA XII). Researchers found that AS1 exhibited the most potent CA IX inhibition with a Ki value of 14.5 nM, while AS2 showed the most potent CA XII inhibition (Ki value: 18.6 nM). For comparison, a standard reference inhibitor of CA, acetazolamide was shown to have a Ki value of 24.6 nM for CA IX and a more potent inhibition of CA XII (Ki = 5.8 nM). Thus, although the urea–sulfonamides derivatives were designed as VEGFR‐2 inhibitors, they exhibit a potential dual profile with several compounds that maintain acceptable selectivity toward normal WI‐38 cells while exhibiting potent VEGFR‐2 inhibition in addition to moderate inhibitory effects on tumor‐associated carbonic anhydrase enzymes, which may contribute to their anticancer activity. Pharmacokinetic predictions implied good drug‐like properties although some of the compounds violated the Lipinski's rule limits. In general, AS5 and AS8 showed very promising characteristics with strong VEGFR‐2 inhibition, selective cytotoxicity and the induction of apoptosis, making them interesting compounds for further studies in anticancer therapy.
Shihan et al. (Mon,) studied this question.