Carbonic anhydrase inhibitors. Aromatic/heterocyclic sulfonamides incorporating phenacetyl, pyridylacetyl and thienylacetyl tails act as potent inhibitors of human mitochondrial isoforms VA and VB

Guzel O. , Innocenti A., Scozzafava A., Salman A., Supuran C. T.

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.17, ss.4894-4899, 2009 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 17 Konu: 14
  • Basım Tarihi: 2009
  • Doi Numarası: 10.1016/j.bmc.2009.06.006
  • Sayfa Sayıları: ss.4894-4899


A series of aromatic/heterocyclic sulfonamides incorporating phenyl(alkyl), halogenosubstituted-phenyl-or 1,3,4-thiadiazole-sulfonamide moieties and thienylacetamido; phenacetamido and pyridinylacetamido tails were prepared and assayed as inhibitors of four physiologically relevant carbonic anhydrase (CA, EC isoforms, the cytosolic human (h) hCA I and hCA II, and the mitochondrial hCA VA and hCA VB. The new compounds showed moderate inhibition of the two cytosolic isoforms (K(I)s of 50-390 nM) and excellent inhibitory activity against the two mitochondrial enzymes, with many low nanomolar inhibitors detected (K(I)s in the range of 5.9-10.2 nM). All substitution patterns explored here lead to effective hCA VA/VB inhibitors. Some hCA VA/VB selective inhibitors were also detected, with selectivity ratios for inhibiting the mitochondrial over the cytosolic isozymes of around 55.5-56.9. As hCA VA/VB are involved in several biosynthetic processes catalyzed by pyruvate carboxylase, acetyl CoA carboxylase, and carbamoyl phosphate synthetases I and II, providing the bicarbonate substrate to these carboxylating enzymes involved in fatty acid biosynthesis, their selective inhibition may lead to the development of antiobesity agents possessing a new mechanism of action. (C) 2009 Elsevier Ltd. All rights reserved.