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Design and synthesis of novel uracil-linked Schiff bases as dual histone deacetylase type II/topoisomerase type I inhibitors with apoptotic potential

    Samar El-Kalyoubi

    *Author for correspondence:

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

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

    ,
    Samar S Elbaramawi

    Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

    ,
    Ahmed G Eissa

    Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

    ,
    Essam Al-Ageeli

    Department of Clinical Biochemistry (Medical Genetics), Faculty of Medicine, Jazan University, Jazan, 82621, Saudi Arabia

    ,
    Yahya Hasan Hobani

    Medical Laboratory Technology Department, College of Applied Medical Sciences, Jazan University, Jazan, 82621, Saudi Arabia

    ,
    Aya Ali El-Sharkawy

    Zoology Department, Faculty of Science, Cairo University, Cairo, 12613, Egypt

    ,
    Hossam Taha Mohamed

    Zoology Department, Faculty of Science, Cairo University, Cairo, 12613, Egypt

    Faculty of Biotechnology, October University for Modern Sciences & Arts, Giza, 12451, Egypt

    ,
    Ahmed A Al-Karmalawy

    **Author for correspondence:

    E-mail Address: akarmalawy@acu.edu.eg

    Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, Egypt

    &
    Hamada S Abulkhair

    Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, 11884, Cairo, Egypt

    Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University-Egypt, International Coastal Road, New Damietta, 34518, Egypt

    Published Online:https://doi.org/10.4155/fmc-2023-0112

    Aim: The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. Materials & methods: We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases (19–30) as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic BAX and antiapoptotic BCL2 genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Results: Compounds 22, 25 and 30 exhibited significant activities. The bromophenyl derivative 22 displayed the best selectivity index, with IC50 values against HDAC II and Topo I of 1.12 and 13.44 μM, respectively. Conclusion: Compound 22 could be considered a lead HDAC II/Topo I inhibitor.

    Graphical abstract

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

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