Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan skeleton, to produce compounds 6a-i and 11a-h, respectively. Among the synthesized compounds, derivatives 6a, 6c, 6e, 6g, 11a, and 11c showed excellent antiproliferative activity, with IC50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6a-g, 6i, 11a, 11c, and 11e, although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.

Department of Chemical Pharmaceutical and Agricultural Sciences University of Ferrara 44121 Ferrara Italy

Department of Organic Chemistry University of Chemistry and Technology Prague 166 28 Prague Czech Republic

Department of Translational Medicine University of Ferrara 44121 Ferrara Italy

Department of Woman's and Child's Health Hemato Oncology Lab University of Padova 35128 Padova Italy

Laboratory of Experimental Pharmacology Istituto di Ricerca Pediatrica Fondazione Città della Speranza 35128 Padova Italy

Medicinal Chemistry Department Integrated Drug Discovery Aptuit an Evotec Company 37135 Verona Italy

Molecular Pharmacology Branch Developmental Therapeutics Program Division of Cancer Treatment and Diagnosis Frederick National Laboratory for Cancer Research National Cancer Institute National Institutes of Health Frederick MD 21702 USA

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