Rhodanine-Piperazine Hybrids as Potential VEGFR, EGFR, and HER2 Targeting Anti-Breast Cancer Agents

Abstract

Breast cancer is one of the most common malignancies affecting women worldwide, with a significant need for novel therapeutic agents to target specific molecular pathways involved in tumor progression. In this study, a series of rhodanine-piperazine hybrids were designed, synthesized, and evaluated for their anticancer activity, targeting key tyrosine kinases such as VEGFR, EGFR, and HER2. Biological screening against breast cancer cell lines (MCF-7, MDA-MB-231, T47D, and MDA-MB-468) revealed 3 of the 13 tested compounds as the most potent, with 5-({4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}methylidene)-2-thioxo-1,3-thiazolidin-4-one (12) showing the strongest activity, particularly against the MCF-7 and MDA-MB-468 cell lines. Molecular docking studies indicated favorable binding interactions of compound 12 and its 3-phenyl-2-thioxo-1,3-thiazolidin-4-one analogue (15) with HER2, VEGFR, and EGFR, and molecular dynamics simulations further confirmed their stable binding to HER2. These findings highlight the potential of rhodanine-piperazine hybrids as promising leads for developing new anticancer agents targeting breast cancer, particularly HER2-positive subtypes. Further structural optimization could enhance their efficacy and therapeutic profile.

Keywords: EGFR; HER2; VEGFR; anti-breast cancer activity; molecular docking; rhodanine–piperazine hybrids.

Figure 1

Design of new rhodanine–piperazine hybrids. Abbreviations: HBA—hydrogen bond acc−eptor; HBD—hydrogen bond donor; and Ar—aryl.

Figure 2

Examples of kinase inhibitors containing a piperazine ring and used as anti-breast cancer drugs.

Scheme 1

Synthesis of rhodanine–piperazine hybrids (5–17). Reagents and conditions: (i) HCl at r.t., then 90 °C, 5 min; (ii) KOH, 0–5 °C; (iii) ClCH₂COOK, 0–5 °C; HCl, 90 °C, 5 min; (iv) Ac₂O, reflux, 3 h; (v) anhydrous ethanol, reflux, 30 min.

Figure 3

Bioavailability radar for rhodanine–piperazine hybrids (5–17). The pink area represents the optimal range for each of the properties (lipophilicity: XLOGP3 between −0.7 and +5.0, size: M between 150 and 500 g/mol, polarity: TPSA between 20 and 130 Ų, solubility: log S not higher than six, saturation: fraction of carbons in the sp³ hybridization not less than 0.25, and flexibility: no more than nine rotatable bonds).

Figure 4

The structure–activity relationship of the tested rhodanine–piperazine hybrids against breast cancer cell lines.

Figure 5

The 3D and 2D schemes of the HER2–compound 12 complex.

Figure 6

The 3D and 2D schemes of the HER2–compound 15 complex.

Figure 7

The comparison of the RMSD values for the 12, 15, and Tak-285 complexes with HER2 (PDB 3RCD).

Figure 8

The calculated average RMSF for HER2 complexes with 12, 15, and Tak-285.

Figure 9

The number of hydrogen bonds during the simulation for complexes of HER2 with 15, Tak-285, and 12.

Figure 10

The Rg values for 15, Tak-285, and 12 complexes with HER2.