Design, synthesis, and antiproliferative activity evaluation of novel N-hydroxyurea derivatives as possible dual HDAC-BET inhibitors

Abstract

Author(s): Hayjaa Mohessen Mosa, Ayad Abed Ali Al-Hamashi

Histone Deacetylase (HDAC) and bromodomain (BET) enzymes represent interesting targets for development of new anticancer molecules. In this work, novel hydroxamates derivative were designed through the implication of modeling docking studies utilizing Glide tool in the Maestro platform 13.0.135, 2021-4 of Schrodinger suite, LLC, New York, 2021 to assess the binding affinity of the designed compounds into HDAC and BET enzymes. Compounds with decent docking scores and virtual dual inhibition activities were selected for synthesis. The proposed molecules were synthesized employing conventional organic synthesis methods through amidation reaction followed by nucleophilic substitution reaction to replace the p-bromo with amine group. The N-hydroxyurea containing final compounds IVa and IVb were afforded using CDI and NH3OH. The ADME properties were virtually assessed utilizing QikProp Schrodinger, New York, NY, 2021. The virtual ADME results were indicated the drug-likeness properties for the final compounds with no major violation for the rule of five. In comparison to vorinostst, compound Vb that involves N-hydroxyurea as Zinc-Binding Group (ZBG), aromatic linker, and sulfonamide cap group showed optimum in silico selectivity and potency toward HDAC2, HDAC6, and HDAC8 (-10.19, -7.00, - 10.87 kcal/mol, respectively), and while interacting into bromodomain (BRD4) with acceptable docking score of -5.48 kcal/mol. The preliminary antiproliferative activity indicated that compounds Va and Vb inhibited the growth of colon cancer cells (LS-174T) in a submicromolar IC50 of 0.47 μM and 0.18 μM, respectively.

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