3-(4-Aroyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 3. Discovery of Novel Lead Compounds through Structure-Based Drug Design and Docking Studies<SUP>,</SUP>

Aroyl-pyrrole-hydroxy-amides (APHAs) are a new class of synthetic HDAC inhibitors recently described by us. Through three different docking procedures we designed, synthesized, and tested two new isomers of APHA lead compound 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (<BO>1</BO>), compounds <BO>3</BO> and <BO>4</BO>, characterized by different insertions of benzoyl and propenoylhydroxamate groups onto the pyrrole ring. Biological activities of <BO>3</BO> and <BO>4</BO> were predicted by computational tools up to 617-fold more potent than that of <BO>1</BO> against HDAC1; thus, <BO>3</BO> and <BO>4</BO> were synthesized and tested against both mouse HDAC1 and maize HD2 enzymes. Predictions of biological affinities (K<INF>i</INF> values) of <BO>3</BO> and <BO>4</BO>, performed by a VALIDATE model (applied on either SAD or automatic DOCK or Autodock results) and by the Autodock internal scoring function, were in good agreement with experimental activities. Ligand/receptor positive interactions made by <BO>3</BO> and <BO>4</BO> into the catalytic pocket, in addition to those showed by <BO>1</BO>, could at least in part account for their higher HDAC1 inhibitory activities. In particular, in mouse HDAC1 inhibitory assay <BO>3</BO> and <BO>4</BO> were 19- and 6-times more potent than <BO>1</BO>, respectively, and <BO>3</BO> and <BO>4</BO> antimaize HD2 activities were 16- and 76-times higher than that of <BO>1</BO>, <BO>4</BO> being as potent as SAHA in this assay. Compound <BO>4</BO>, tested as antiproliferative and cytodifferentiating agent on MEL cells, showed dose-dependent growth inhibition and hemoglobin accumulation effects.