# Synthesis and Development of 3-((2,4-Difluorophenyl)Amino)Propanoic Acid Derivatives as an Antiproliferative Medicinal Chemistry Scaffold Targeting Growth Factor Receptors

## TL;DR

This study designs and tests new compounds that show strong cancer cell growth inhibition by targeting specific receptor proteins involved in tumor progression.

## Contribution

The paper introduces a novel scaffold of 3-[(2,4-difluorophenyl)amino]propanoic acid derivatives with antiproliferative activity against cancer cells.

## Key findings

- Compounds 6b, 7f, 7g, and 9 reduced cancer cell viability by about 50% in A549 and Caco-2 cell lines.
- Molecular docking showed compound 9 binds effectively to c-MET and HER2 with favorable interactions.
- Active compounds showed cytotoxicity in HEK293 cells similar to doxorubicin and cisplatin.

## Abstract

Background/Objectives: The development of novel small-molecule kinase inhibitors remains an important strategy in anticancer drug discovery. Receptor tyrosine kinases such as c-MET and HER2 are clinically relevant targets involved in tumor progression and resistance mechanisms. The aim of this study was to design, synthesize, and biologically evaluate a series of 3-[(2,4-difluorophenyl)amino]propanoic acid derivatives as potential antiproliferative agents and to explore their possible interactions with selected kinase targets. Methods: A series of ester, hydrazide, hydrazone, semicarbazide, triazolone, and triazolethione derivatives (2–21) were synthesized and structurally characterized by NMR, IR spectroscopy, and microanalysis. The compounds were evaluated for in vitro anticancer activity against A549 and Caco-2 human cancer cell lines. In addition, molecular docking studies were performed to investigate binding interactions with c-MET and HER2 receptor tyrosine kinases. Cytotoxicity toward non-transformed HEK293 cells was also assessed. Results: The synthesized derivatives demonstrated structure–activity relationships, with compounds 6b, 7f, 7g, and 9 exhibiting the most pronounced antiproliferative effects, reducing cancer cell viability by approximately 50% in both tested cell lines. Molecular docking indicated that compound 9 displayed favorable predicted binding energies toward c-MET and HER2, forming hydrophobic and hydrogen-bond interactions within the active sites and showing overlapping contacts with native ligands and reference inhibitors. Active compounds also demonstrated cytotoxic effects in HEK293 cells comparable to those of doxorubicin and cisplatin. Conclusions: These results identify 3-[(2,4-difluorophenyl)amino]propanoic acid derivatives, particularly compound 9, as promising scaffolds for further structural optimization toward the development of kinase-targeting antiproliferative agents.