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

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

  • Pharmaceuticals (Basel). 2026 Feb 27;19(3):381. doi: 10.3390/ph19030381.
Guoda Pranaitytė 1,  Povilas Kavaliauskas 1 2 3,  Vidmantas Petraitis 4,  Rūta Petraitienė 4,  Ramunė Grigalevičiūtė 3 5,  Liudas Ivanauskas 6,  Mindaugas Marksa 6,  Gediminas Duda 6,  Waldo Acevedo 7 8,  Birutė Grybaitė 1,  Vytautas Mickevičius 1
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Kaunas University of Technology, Radvilenu˛ Rd. 19, LT-50254 Kaunas, Lithuania.
  • 2 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • 3 Biological Research Center, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania.
  • 4 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA.
  • 5 Department of Animal Nutrition, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania.
  • 6 Department of Analytical and Toxicological Chemistry, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania.
  • 7 Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile.
  • 8 Center for Interdisciplinary Research in Biomedicine, Biotechnology and Well-Being (CID3B), Pontificia Universidad Católica de Valparaíso, Valparaíso 2340025, Chile.
PMID: 41901229 DOI: 10.3390/ph19030381
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.

Keywords

2,4-difluorophenyl moiety; antiproliferative activity; azoles; hydrazones; β-amino acid.

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