2. Academic Validation
  3. Novel coumarin-6-sulfonamide-chalcone hybrids as glutathione transferase P1-1 inhibitors

Novel coumarin-6-sulfonamide-chalcone hybrids as glutathione transferase P1-1 inhibitors

  • PLoS One. 2024 Aug 14;19(8):e0306124. doi: 10.1371/journal.pone.0306124.
Ahmed Sabt 1,  Stefanos Kitsos 2,  Manal S Ebaid 3,  Veronika Furlan 4,  Panagiota D Pantiora 2,  Magdalini Tsolka 2,  Eslam B Elkaeed 5,  Mohamed Farouk Hamissa 6,  Nikolaos Angelis 7,  Ourania E Tsitsilonis 7,  Anastassios C Papageorgiou 8,  Urban Bren 4 9 10,  Nikolaos E Labrou 2
Affiliations

Affiliations

  • 1 Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Center, Dokki, Cairo, Egypt.
  • 2 Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece.
  • 3 Department of Chemistry, College of Science, Northern Border University, Arar, Saudi Arabia.
  • 4 Faculty of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Diriyah, Saudi Arabia.
  • 6 Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Prague, Czech Republic.
  • 7 Section of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
  • 8 Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
  • 9 Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Koper, Slovenia.
  • 10 Institute of Environmental Protection and Sensors, Maribor, Slovenia.
PMID: 39141629 DOI: 10.1371/journal.pone.0306124
Abstract

Multidrug resistance (MDR) mechanisms in Cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target Enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate Cancer cell lines DU-145 and PC3, as well as the breast Cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for Anticancer purposes.

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