Direct and Indirect DNA Targeting by Arylidene Hydrazinyl Thiazole Hybrids

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Authors

1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.

2 Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt.

3 Department of Organic Chemistry, Medical University of Bialystok, Bialystok, Poland.

4 Department of Physical Chemistry, University of Bialystok, Institute of Chemistry, Bialystok, Poland.

5 Institute of Organic Chemistry, Lodz University of Technology, Lodz, Poland.

Abstract

In light of searching for new breast cancer therapies, DNA-targeted small molecules were rationally designed to simultaneously bind DNA and inhibit human dihydrofolate reductase (hDHFR). Fourteen new arylidene-hydrazinyl-1,3-thiazoles were synthesized and their dual DNA groove binding potential and in vitro hDHFR inhibition were performed. Two compounds proved their dual efficacy. Molecular docking and molecular dynamics simulations were performed for those active derivatives to explore their mode of binding and stability of interactions inside DHFR active site. Anti-breast cancer activity was assessed  on MCF-7 cells using MTX as reference. IC50 measurements revealed that both compounds were more potent and selective than MTX. Cytotoxicity was examined against normal skin fibroblasts to examine safety and selectivity. Moreover, mechanistic studies including apoptosis induction and wound healing were performed. Further in silico ADMET assessment was conducted to determine their eligibility as drug leads suitable for future optimization and development.

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Alexandria Journal of Science and Technology
Volume 3, Issue 2 - Serial Number 2
Special Issue (Conference Presentations): The Role of Organic, Medicinal, and Pharmaceutical Chemistry in Small Molecule Discovery for Biomedical Applications
September 2025
Pages 126-126

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