2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel 6-(4-aminopiperidin-1-yl)-substituted benzyl-3-methylpyrimidine-2,4(1H,3H)-dione derivatives as potential anticancer agents targeting thymidylate synthase

Design, synthesis, and biological evaluation of novel 6-(4-aminopiperidin-1-yl)-substituted benzyl-3-methylpyrimidine-2,4(1H,3H)-dione derivatives as potential anticancer agents targeting thymidylate synthase

  • Sci Rep. 2025 Nov 20;15(1):40991. doi: 10.1038/s41598-025-24828-5.
Ladan Baziar # 1,  Elaheh Ataollahi # 2,  Zahra Rezaei 1,  Yousif Abdulkadhim 3,  Mohammad Reza Abdolahi 3,  Alireza Poustforoosh 4,  Somayeh Zare 5,  Mina Emami 2,  Maryam Moghtader Mansouri 1,  Leila Emami 6,  Soghra Khabnadideh 7 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 2 Pharmaceutical Sciences Research Center, Faculty of pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 3 Student Research Committee, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 4 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 5 Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hormozgan University of Medical Sciences, Hormozgan, Iran.
  • 6 Pharmaceutical Sciences Research Center, Faculty of pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. [email protected].
  • 7 Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. [email protected].
  • 8 Pharmaceutical Sciences Research Center, Faculty of pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. [email protected].
  • # Contributed equally.
PMID: 41266472 DOI: 10.1038/s41598-025-24828-5
Abstract

This study was undertaken to identify novel Thymidylate Synthase inhibitors with improved efficacy and selectivity over existing chemotherapeutics. A series of novel 6-(4-aminopiperidin-1-yl)-substituted benzyl-3-methylpyrimidine-2,4(1 H,3 H)-dione derivatives were designed, synthesized, and evaluated as potential Anticancer agents. Among these, compound 5 h exhibited the most potent cytotoxicity, with IC50 values of 15.70 ± 0.28 µM and 16.50 ± 4.90 µM against SW480 (colorectal Cancer) and MCF-7 (breast Cancer) cell lines, respectively, which were comparable to cytometry demonstrated that 5 h significantly induced Apoptosis in a dose-dependent manner (up to 62% at 32 µM) and caused marked S-phase cell cycle arrest. Molecular docking and 100-ns molecular dynamics (MD) simulations revealed strong and stable interactions of 5 h with the active site of Thymidylate Synthase (TS), primarily through hydrogen bonding with Asp218 and Met311. MM/GBSA analysis further supported a favorable binding free energy profile. Density functional theory (DFT) studies indicated that 5 h possessed lower Gibbs free energy and higher electron affinity than less active analogs, suggesting enhanced binding and biological stability. binding affinity predictions showed that all derivatives met Lipinski's criteria and had favorable intestinal absorption exhibited permeability. Collectively, these results highlight 5 h as a promising lead for further preclinical evaluation as a Thymidylate Synthase Inhibitor and Anticancer agent.

Keywords

Apoptosis; Cell cycle arrest; Molecular dynamics; Piperidine; Pyrimidine; Thymidylate synthase.

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