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New thiouracil derivatives as histone deacetylase inhibitors and apoptosis inducers: design, synthesis and anticancer evaluation

    Omnia R Elbatrawy

    Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, 11754, Egypt

    ,
    Moshira A El Deeb

    Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, 11754, Egypt

    ,
    Mohamed Hagras

    Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt

    ,
    Fatimah Agili

    Chemistry Department, Faculty of Science (Female Section), Jazan University, Jazan, 82621, Saudi Arabia

    ,
    Maghawry Hegazy

    Biochemistry & Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt

    ,
    Ahmed A El-Husseiny

    Biochemistry & Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt

    Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, 11829, Cairo, Egypt

    ,
    Mohamed A Elkady

    Biochemistry & Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt

    ,
    Ibrahim H Eissa

    **Author for correspondence:

    E-mail Address: ibrahimeissa@azhar.edu.eg

    Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt

    &
    Samar El-Kalyoubi

    *Author for correspondence:

    E-mail Address: s.elkalyoubi@hotmail.com

    Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, 42511, Port Said, Egypt

    Published Online:https://doi.org/10.4155/fmc-2023-0106

    Background: Histone deacetylase (HDAC) inhibitors have good contributions in cancer management. Aim: To introduce new active HDAC inhibitors. Methods: Design and synthesis of 16 thiouracil derivatives with deep biological and computational investigation. Results: Compounds 7a, 7c, 7d, 7e, 8a and 8f showed the highest antiproliferative effects against MCF7, HepG2 and HCT116 cell lines. Compound 7e exhibited the highest activities against HDAC1 and HDAC4. Compound 7e arrested the cell cycle of HCT116 cells at G0–G1 with significant apoptotic effect. In addition, treatment with compound 7e was associated with a significant increase in the levels of caspase-3 and caspase-8. The docking studies gave good insight about the binding patterns of the synthesized compounds against HDAC1. Conclusion: Compound 7e has a promising anticancer activity targeting HDAC.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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