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Current Bioactive Compounds


ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Research Article

Design, Synthesis and Biological Activity of New Hydroxamic Acids Containing 2-Imidazolylphenyl(oxy/thio)alkanoic Fragment

Author(s): Desislava V. Stanisheva, Gjorgji Atanasov, Margarita D. Aposstolova and Ognyan I. Petrov *

Volume 17, Issue 1, 2021

Published on: 14 February, 2020

Page: [59 - 66] Pages: 8

DOI: 10.2174/1573407216666200214093400

Price: $65


Background: Histone Deacetylase (HDAC) inhibitors are a new class of therapeutic compounds that show promising results in a series of preclinical and clinical anticancer studies. Hydroxamic acids belong to one of the most significant classes of HDAC inhibitors. The member vorinostat (SAHA) was approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma.

Methods: A series of eight novel hydroxamic acids containing 2-imidazolylphenyl(oxy/thio) alkanoic fragment designed to target Histone Deacetylase (HDAC) were synthesized in five steps from easily accessible 2(3H)-benzoxazolones and 2(3H)-benzthiazolones. The newly synthesized compounds were characterized by 1H, 13C NMR, and elemental analysis.

Results: The structure-activity relationship was examined via linker length alternation and variation of the heteroatom (oxygen or sulfur) and chlorine substitution pattern of the starting materials. The compounds were tested for their cytotoxic activity against two human cancer cell lines (HT-29 and MDA-MB-231). Our data indicate that the compound 6.1d is active in the micromolar range with IC50 of 9.7 μM for MDA-MB-231 cells. DNA fragmentation analysis of the most active compounds confirmed that apoptosis could be one of the mechanisms involved in cell death.

Conclusion: Taken together, the results revealed that 6d may become a promising lead compound for new anticancer drugs discovery.

Keywords: Hydroxamic acids, HDAC inhibitors, imidazolone, benzoxazolone, ring transformation, nucleosomal histones.

Graphical Abstract
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