3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides, a new class of synthetic histone deacetylase inhibitors

Novel 3-(4-aroyl-2-pyrrolyl)-N-hydroxy-2-propen- amides are disclosed as a new class of histone deacetylase (HDAC) inhibitors. Three-dimensional struc ture-based drug design and conformational analyses into the histone deacety lase-like protein (HDLP) catalytic core suggested the synthesis and biologi cal evaluation of compounds 7a-h. Experimental pK(i) values are in good agr eement with VALIDATE predicted pK(i) values of new derivatives. All compoun ds 7a-h show HDAC inhibitory activity in the micromolar range, with 7e as t he most potent derivative (IC50 = 1.9 muM). The influence of the 4'-substit uent in the aroyl moiety is not significant for the inhibitory activity, as all compounds 7a-g show IC50 values between 1.9 and 3.9 muM. Otherwise, th e unsaturated chain linking the pyrrole ring to the hydroxamic acid group i s clearly important for the anti-HDAC activity, the saturated analogue 7h b eing 10-fold less active than the unsaturated counterpart 7a.