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Innovative Amino-Functionalization of Pyrido[2,3- d ]pyrimidine Scaffolds for Broad Therapeutic Applications Supported by Computational Analyses.

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Titel:	Innovative Amino-Functionalization of Pyrido[2,3- d ]pyrimidine Scaffolds for Broad Therapeutic Applications Supported by Computational Analyses.
Autoren:	El-Hema, Hagar S., Shehata, Haitham E., Hawata, Mohamed A., Nossier, Eman S., El-Sayed, Ahmed F., Altwaijry, Najla A., Saleh, Asmaa, Hussein, Modather F., Sabry, Amr, Abdel-Rahman, Adel A.-H.
Quelle:	Pharmaceuticals (14248247); Oct2025, Vol. 18 Issue 10, p1472, 39p
Schlagwörter:	ANTIBACTERIAL agents, ANTINEOPLASTIC agents, TREATMENT effectiveness, MOLECULAR dynamics, EPIDERMAL growth factor receptors, PYRIMIDINES, QUANTITATIVE research
Abstract:	Background: Derivatives of Pyrido[2,3-d]pyrimidine-6-carboxylate are promising multi-target scaffolds. This study focused on synthesizing 16 amino-functionalized derivatives and evaluating their dual anticancer and antibacterial activities, supported by mechanistic and computational analyses. Objectives: Design and synthesize derivatives, evaluate cytotoxicity against HeLa, HepG-2, and MCF-7 (selectivity against WI-38), investigate EGFR^WT and EGFR^T790M inhibition, assess cell cycle, apoptosis, and migration effects, antibacterial efficacy against E. coli and P. aeruginosa, and perform in silico ADMET, docking, molecular dynamics, DFT, and antiviral predictions. Methods: Synthesized 16 derivatives; tested for cytotoxicity, EGFR inhibition, cell cycle, apoptosis, migration; assessed antibacterial activity; performed ADMET profiling, molecular docking, molecular dynamics, and DFT calculations. Results: Derivatives 1, 2, and 7 showed highest cytotoxicity (IC50 = 3.98–17.52 μM; WI-38 IC50 = 64.07–81.65 μM). Compound 1 potently inhibited EGFRWT (IC50 = 0.093 μM) and EGFRT790M (IC50 = 0.174 μM), induced G0/G1 arrest (74.86%) and apoptosis (26.37%), and reduced MCF-7 migration (69.63%). Moderate antibacterial activity observed (MIC = 50 μg/mL). ADMET indicated favorable pharmacokinetics, low CYP inhibition, negative mutagenicity, and oral toxicity class III. Molecular dynamics confirmed stable binding (EGFRWT RMSD 3 Å; EGFRT790M 3.5–4.6 Å) with persistent hydrogen bonds. In silico antiviral evaluation suggested strong binding to HCV NS5A (–9.36 kcal/mol), SARS-CoV-2 Mpro (–9.82 kcal/mol), and E.coli DNA gyrase (–10.25 kcal/mol). Conclusions: Compound 1 exhibits dual anticancer and antibacterial activity, supported by mechanistic and computational analyses, highlighting pyrido[2,3-d]pyrimidines as promising multi-target therapeutic scaffolds. [ABSTRACT FROM AUTHOR]
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Datenbank:	Biomedical Index

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