Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.

Département de Biologie Structurale Intégrative Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS INSERM Université de Strasbourg CEDEX 67404 Illkirch France

Department of Enzymology Institute of Biochemistry Martin Luther University of Halle Wittenberg 06120 Halle Germany

Department of Medicinal Chemistry Institute of Pharmacy Martin Luther University of Halle Wittenberg 06120 Halle Germany

Department of Pharmaceutical Chemistry Faculty of Pharmacy Alexandria University Alexandria 21521 Egypt

Department of Pharmaceutical Chemistry Faculty of Pharmacy Egyptian Russian University Badr City Cairo 11829 Egypt

Department of Toxicology University Medical Center 55131 Mainz Germany

Department of Zoology Faculty of Science Aswan University Aswan 81528 Egypt

Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Prumyslova 595 25250 Vestec Czech Republic

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