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-propenamides are disclosed as a new class of histone deacetylase (HDAC) inhibitors. Three-dimensional structure-based drug design and conformational analyses into the histone deacetylase-like protein (HDLP) catalytic core suggested the synthesis and biological evaluation of compounds 7a-h. Experimental pK(i) values are in good agreement with VALIDATE predicted pK(i) values of new derivatives. All compounds 7a-h show HDAC inhibitory activity in the micromolar range, with 7e as the most potent derivative (IC(50) = 1.9 microM). The influence of the 4'-substituent in the aroyl moiety is not significant for the inhibitory activity, as all compounds 7a-g show IC(50) values between 1.9 and 3.9 microM. Otherwise, the unsaturated chain linking the pyrrole ring to the hydroxamic acid group is clearly important for the anti-HDAC activity, the saturated analogue 7h being 10-fold less active than the unsaturated counterpart 7a.
Massa
S
S
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, via Aldo Moro, 53100 Siena, Italy. S.M.massa@unisi.it
Mai
A
A
Sbardella
G
G
Esposito
M
M
Ragno
R
R
Loidl
P
P
Brosch
G
G
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011758:Pyrroles; D006655:Histone Deacetylases